Dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to novel compounds representated by formula (I), where R, R1, R2, R3, X, Y, m, n are as defined. The present invention relates to compounds of the general formula I their derivatives, their analogs, their tautomeric forms, their stereoisomers, their diastereomers, their bioisosteres, their polymorphs, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them which are predominantly dipeptidyl peptidase IV inhibitors. The present invention also relates to the processes for the preparation of novel compounds of formula (I) and their use in treating type II diabetes and diabetic complications thereof and also for treating dislipidemia, hypercholesterolemia, obesity and hyperglycemia.

This application claims the benefit of Indian Application No.610/CHE/2006 filed Apr. 3, 2006 and U.S. Provisional Application No. USA60/801,437, filed May 18, 2006, both of which are hereby incorporated byreference.

FIELD OF INVENTION

The present invention relates to novel compounds represented by formulaI, their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their bioisosters, their diastereomers, their polymorphs,their pharmaceutically acceptable salts, solvates and pharmaceuticallyacceptable compositions containing them, which are useful in treatingtype II diabetes and diabetic complications as well as for the treatmentof dislipidemia, hypercholesterolemia, obesity, and hyperglycemia.

More specifically, the present invention relates to the compounds offormula I, which are predominantly serine protease inhibitors,particularly dipeptidyl peptidase inhibitors, more particularlydipeptidyl peptidase IV inhibitors, as well as to their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirbioisosters, their diastereomers, their polymorphs, theirpharmaceutically acceptable salts, and solvates. Additionally, thepresent invention relates to pharmaceutically acceptable compositionscontaining the aforementioned compounds.

The compounds of the present invention are represented by formula I

its derivatives, analogs, tautomeric forms, stereoisomers, bioisosters,diastereomers, polymorphs, pharmaceutically acceptable salts andpharmaceutically acceptable solvates, wherein:

X=CH₂, CHF, CF₂, CHCl, CHOH, CHOCH₃, NH, NCOCH₃, CHPh, O, or S,

Y=CN,

R₁ and R₅ are selected from hydrogen, C₁-C₄ alkyl, and hydroxy,

R₂ is selected from hydrogen, C₁-C₄ alkyl, substituted alkyl, C₁₋₄alkoxy C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, R₅NHC₁₋₄ alkyl, andR₅NHC(NH)NHC₁₋₄ alkyl,

R₃ is selected from hydrogen and C₁-C₄ alkyl,

R₄ is selected from hydrogen, C₁-C₄ alkyl, substituted alkyl, C₁-C₄alkoxy, C₁-C₄ alkanoyloxy, hydroxy, amino, nitro, C₂-C₆ alkenyl, acyl,and halogen,

n=1 or 2,

m=0, 1, or 2,

R=R₁₁, R₁₂, or R₁₃, in which

R₁₁ comprises at least one of the groups selected from below a), b), orc), whereupon the optionally substituted cycloalkyl, heterocyclyl, andheteroaryl groups are linked to the nor-adamantyl moiety either directlyor via a methylene or ethylene adjacent, either by C—C linkage or by C—Nlinkage.

a) A cycloalkyl group, which is optionally substituted by C₁-C₄ alkyl,dialkyl, or oxo, preferably a C₄-C₇ ring system, more preferably a C₅-C₆ring system, which may be further functionalized or substituted withmultiple degrees of substitution. Examples of possible cycloalkyl groupsare cyclopentane, cyclohexane, cyclopentane dione, cyclohexane dione andthe possible substitutions include C₁-C₄ alkyl, dialkyl, and oxo.

b) An optionally substituted heteroaryl group, preferably a 5 to 10membered ring system, in which the heteroaryl ring is a monocyclicaromatic ring system or a bicyclic aromatic ring system comprising one,two, or more heteroatoms selected from nitrogen, sulfur, and oxygen.Possible heteroaryl groups include but not limited to tetrazole,triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole,furan, benzofuran, benzimidazole, indazole, thiophene, andbenzothiophene and the substitutions on the heteroaryl ring may be thesame or different and are selected from R₆ and R₇, wherein R₆ ishydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, hydroxy alkyl,alkylamino, haloalkyl, amino, acyl, COOR₉, or COR₉, and R₇ is selectedfrom a group consisting of hydrogen, hydroxy, halogen, amino, nitro,C₁-C₈ alkyl, C₂-C₄ alkenyl, COOR₉, CONR₈R₉, COR₉, NHCOOR₈, NHS(O)₂R₈,NHS(O)R₈, NHS(O)₂NHR₈, NR₈COOR₉, NR₈COR₉, NR₈S(O)₂R₉, NR₈CONR₈R₉,NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, OSO₂R₈, OCONR₈R₉, SO₂R₈, SOR₈, SR₈,SO₂NR₈R₉, and S(O)₂OR₈. When R₆ and R₇ are present on adjacent carbonatoms of the ring system, they may together form a six membered aromaticring such as phenyl or a heterocyclic ring such as pyridine with furthersubstitutions such as amino, hydroxy, alkyl, alkyl sulfonyl, alkyl thio,alkyl sulfinyl, carboxy, or oxo.

c) A heterocyclyl group optionally substituted by C₁-C₃ alkyl, dialkyland oxo groups, wherein the heterocyclic ring system is a 4- to10-membered mono- or bicyclic ring system with one or more heteroatomsselected from the group consisting of nitrogen, sulfur, and oxygen,wherein the heteroatoms can also be present as functional groups, suchas N-oxides, sulfur oxides, and sulfur dioxides, wherein theheterocyclic ring system may contain one or two double bonds, andwherein the monocyclic heterocyclic ring may be optionally fused to aheteroaryl, aryl, or a cycloalkyl ring optionally substituted with C₁-C₅alkyl, halogens, hydroxy, amino, nitro, haloalkyl, alkylamino, carboxy,NH(CO)R₈, NHS(O)₂R₈, NHC(O)NHR₉, NHSOR₈, NHS(O)₂NHR₈, NR₈COOR₉, NR₈COR₉,NR₈S(O)₂R₉, NR₈CONR₈R₉, NR₈C(S)NR₈R₉, or NHC(O)NHS(O)₂R₈. Examples ofsuch heterocyclic ring radicals include but are not limited toimidazolidinone, isothiazolidine-1,1-dioxide, pyrrolidine,pyrrolidinedione, oxopyrrolidine, isoxazolidinedione, isoindoledione,morpholine, thiomorpholine, thiomorpholine-1,1-dioxide,thiophene-1,1-dioxide, thiazolidinedione, piperidine, piperazine,tetrahydro pyrimidinone, [1,2]-thiazinane-1,1-dioxide, tetrahydrothiophene-1,1-dioxide, piperidinone, andtetrahydrothiopyran-1,1-dioxide.

R₁₂ is selected from hydrogen, halogen, haloalkyl, hydroxy, carboxy,nitro, amino, cyano, alkyl sulfinyl, alkylsulfonyl, alkylthio, amidinyl,alkoxy, alkoxy carbonylamino, ureido, thiureido, alkanoyl, alkanoyloxy,alkanoyl amino, carbamoyl, guanidyl, optionally substituted C₁-C₈ alkyl,and C₂-C₆ alkenyl.

R₁₃ is optionally substituted aryl, wherein the substituents may be thesame or different and comprises at least one of the groups selected from

a) hydrogen;

b) C₁-C₈ alkyl, C₂-C₆ alkenyl, halo, alkylhalo, alkoxy, alkylsulfonyl,alkylsulfinyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbonylamino,guanidyl, nitro, amino, COOR₉, R₈NHC(O)R₉, COR₉, CONR₈R₉, NHC(O)OR₈,NHC(O)R₈, NHC(O)NR₈R₉, NHC(O)NR₈R₉, NHS(O)₂R₈, NHS(O)R₈, NHS(O)₂NHR₈,NHS(O)₂NHC(O)R₈, NR₉COOR₉, NR₈COR₉, NR₉S(O)₂R₉, NR₈CONR₈R₉,NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, S(O)₂R₈, SOR₈, SR₈, S(O)₂NR₈R₉, OCF₃,OS(O)₂R₈, or OC(O)NR₈R₉.

c) Saturated, partially saturated, or unsaturated, mono- or bicyclicheterocyclic ring system optionally substituted by one or more groupsselected from C₁-C₃ alkyl, C₂-C₆ alkenyl, dialkyl, and oxo, wherein theheterocyclic ring system is a 4- to 10-membered ring with one or moreheteroatoms selected from the group consisting of nitrogen, sulfur, andoxygen, wherein the heteroatoms can also be present as functionalgroups, such as N-oxides, sulfur oxides, and sulfur dioxides. Examplesof such heterocyclic ring radicals include, but are not limited topyridine, pyrimidine, imidazolidinone, imidazolidinethione, indazole,indole, isoindole, quinazoline, quinoline, isoquinoline, cinnalone,isothiazolidine-1,1-dioxide, pyrrolidinone, 2-piperidinone,tetrahydropyrimidinone, azitidinone, and thiazane-1,1-dioxide.

The R₈, R₉, and R₁₀-groups, which are optionally substituted by halogen,hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy, hydroxyalkyl,amino, alkylthio, or thioalkyl groups, may be the same or different andare individually selected from hydrogen, optionally substituted C₁-C₈alkyl, aryl, arylalkyl, alkoxy carbonyl, and arylalkoxy carbonyl. WhenR₈ and R₉ are present together on a nitrogen atom they may form a 5- or6-membered saturated, partially unsaturated, or unsaturated cyclicsystem containing carbon atoms, at least one nitrogen atom andoptionally one or more other heteroatoms selected from oxygen, sulfur,and nitrogen.

The present invention also relates to a process for the preparation ofcompounds of formula I, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their bioisosters, theirdiastereomers, their polymorphs, their pharmaceutically acceptablesalts, and their solvates.

The present invention also relates to novel intermediates, processes fortheir preparation, their use in the preparation of compounds of formulaI, and their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their bioisosters, their diastereomers, their polymorphs,their pharmaceutically acceptable salts, and their solvates.

BACKGROUND OF THE INVENTION

Diabetes is characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. There are two types of diabetes.Type 1 diabetes is usually diagnosed in children and young adults, andwas previously known as juvenile diabetes. In type 1 diabetes, the bodydoes not produce insulin. Type 2 diabetes is the most common form ofdiabetes. In type 2 diabetes, either the body does not produce enoughinsulin or the cells ignore the insulin. Patients with type 2 diabetesare at increased risk of macro vascular and micro vascularcomplications, including coronary artery disease, stroke, hypertension,nephropathy, peripheral vascular disease, neuropathy, and retinopathy.

A significant, rapidly growing fraction of the human population isaffected by type 2 diabetes, a disease characterized by elevated bloodglucose levels and relative insufficiency of insulin. Recentlyresearches found that the activity of two potent stimulators of insulinsecretion, GLP-1 and GIP, is rapidly abolished by the serine peptidasedipeptidyl peptidase IV (DPP-IV). DPP-IV is a member of a family ofserine peptidases. CD26 or DPP-IV is a membrane-associated peptidase of766 amino acids that is widely distributed in numerous tissues. DPP-4also exists as a soluble circulating form in plasma and significantDPP-4-like activity is detectable in plasma from humans and rodents. Theprincipal biological activity of CD26 (DPP-IV) is its enzymaticfunction. DPP-IV prefers substrates with an amino-terminal proline oralanine at position 2, but may also cleave substrates with non-preferredamino acids at position 2. The structure of GIP, GLP-1 and GLP-2 revealsa highly conserved alanine at position 2, rendering these peptides idealputative substrates for the aminopeptidase dipeptidyl peptidase 4(DPP-4). Eur J Biochem. 1993, 214(3), 829-35.

A glance at the available treatments for type 2 diabetes, which have notchanged substantially in many years, makes clear that they all havetheir own limitations. There are many pharmacologic strategies toaccomplish these goals. First of this series are alpha glucosidaseinhibitors such as acarbose and miglitol, which function by interferingwith the action of the alpha-glucosidases present in the smallintestinal brush border. The consequence of this inhibition is areduction in digestion and the consequent absorption of glucose into thesystemic circulation. The reduction in glucose uptake allows thepancreatic beta-cells to regulate the insulin secretion moreeffectively. The advantage of the use of the alpha-glucosidaseinhibitors is that they function locally in the intestine and have nomajor systemic action. Hypoglycemia does not usually occur with the useof alpha-glucosidase inhibitors but they are effective in reducingfasting plasma glucose (FPG) levels and levels of glycosylatedhemoglobin (HbA_(1c)). The common adverse side effects of theseinhibitors are abdominal bloating and discomfort, diarrhea, andflatulence.

The sulfonylureas and meglitinide classes of oral hypoglycemic drugs arereferred to as endogenous insulin secretagogues because they induce thepancreatic release of endogenous insulin. Because these drugs can inducepronounced hypoglycemia, treatment is initiated with the lowest possibledose and carefully monitored until the dose results in a FPG of 110-140mg/dL. Sulfonylureas function by binding to and inhibiting thepancreatic ATP-dependent potassium channel that is normally involved inglucose-mediated insulin secretion. Sulfonylureas have no significanteffects on circulating triglycerides, lipoproteins, or cholesterol. Thenon-sulfonylurea insulin secretagogues are both fast acting and of shortduration. However, meglitinides (non-sulfonylurea insulin secretagogues)do exert effects on potassium conductance. Like the sulfonylureas, themeglitinides have no direct effects on the circulating levels of plasmalipids.

The biguanides lower serum glucose levels by enhancing insulin-mediatedsuppression of hepatic glucose production and enhancinginsulin-stimulated glucose uptake by skeletal muscle. Metformin is amember of this class and is currently the most widely prescribedinsulin-sensitizing drug in clinical use. Metformin administration doesnot lead to increased insulin release from the pancreas and as such therisk of hypoglycemia is minimal. Because the major site of action formetformin is the liver its use can be contraindicated in patients withliver dysfunction. In adolescent females with type 2 diabetes, the useof metformin is highly recommended to reduce the incidence as well asthe potential for polycystic ovarian syndrome. However the twobiguanides, phenformin and metformin can induce lactic acidosis andnausea/diarrhea.

The peroxisome proliferator-activated nuclear receptor (PPAR) family hasreceived particular scrutiny in the field of diabetes and as a resultthe thiazolidinediones have emerged as a therapeutic class. Firstgeneration thiazolidinediones were agonists of the PPAR gamma receptorand were able to reduce insulin resistance. One adverse effectassociated with PPAR gamma receptor agonists is however weight gain.More recently molecules have been developed that activate PPAR alpha.This class is able to reduce triglyceride levels and is also able toimprove insulin sensitivity and as a result dual PPAR alpha/PPAR gammaagonists have been developed with proposed beneficial effects overexisting PPAR gamma- and alpha-preferential drugs in treatment of type 2diabetes. But safety issues slowed down the entry of these drugs

One of the exciting classes of agents in development are GLP-1 agonists.The primary metabolic responses to GLP-1 release from theenteroendocrine L-cells of the gut are inhibition of glucagon secretionand enhancement of glucose-dependent insulin release from the pancreas,both effects lead to decreased glycemic excursion. But the hormonalaction of GLP-1 is rapidly terminated as a consequence of enzymaticcleavage by DPP IV. Recent clinical evidence has shown that eitherinfusion of GLP-1 or inhibition of DPP IV can result in dramaticreductions in plasma glucose concentrations, reductions in HbA_(1c), andimprovement in pancreatic beta-cell function. Thus, both representpotential targets for the prevention of the hyperglycemia associatedwith diabetes and impaired insulin function. There are advantages anddisadvantages with the current therapeutic approaches targeting GLP-1action in diabetic patients. Current use of GLP-1 mimetics and/or GLP-1receptor (GLP-1R) agonists focus on peptides or modified peptides andthese must be given by injection, which leads to problems with thepatient-compliance.

Another novel mechanism for the treatment of type 2 diabetes areDipeptidyl peptidase-IV inhibitors. Dipeptidyl peptidase IV is amultifunctional protein involved in cleaving incretin hormones, henceserving to regulate glucose homeostasis and consequently viewed as atarget for the management of Type 2 diabetes. The usefulness ofDipeptidyl peptidase IV in the treatment of Type 2 diabetes is based onthe fact that Dipeptidyl peptidase IV in vivo readily inactivates GLP-1and GIP. These are the incretins that are produced when food isconsumed. These incretins stimulate production of insulin. Inhibition ofDipeptidyl peptidase IV leads to decreased inactivation of incretins, inturn increased efficacy of incretins in stimulating insulin productionby pancreas. Therefore Dipeptidyl peptidase IV inhibition results in anincreased level of serum insulin. An interesting observation is thatincretins are produced only when food is consumed. So the Dipeptidylpeptidase IV inhibition is not expected to increase the level of insulinbetween meals which can lead to hypoglycemia. Inhibition of Dipeptidylpeptidase IV is therefore expected to increase insulin withoutincreasing the risk of hypoglycemia. Investigational Dipeptidylpeptidase IV inhibitors offer an advantage over other novel therapiessince they can be administered orally. Compliance in patients is muchhigher with orally delivered drugs than with those that requireinjection. Thus Dipeptidyl peptidase IV inhibitors are a promising newapproach to treat type 2 diabetes, which function, at least in part, asindirect stimulators of insulin secretion. Mechanism and use of DPPIVinhibitors in various diseases is well explained in prior art patentslike WO 2005/033106 and is herein incorporated by reference in itsentirety.

PRIOR ART

International patent application WO 00/34241 discloses the compounds ofthe generic formula

wherein R is substituted adamantyl.

International patent application WO 03/04498 discloses the compounds ofthe generic formula

US-application US 2005/038020 discloses the compounds of generic formula

wherein A is an optionally substituted adamantyl group.

International patent application WO 2006/090244 discloses the compoundsof formula

wherein n is 0, 1, 2, or 3.

R2 is substituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheteroarylalkyl, —NR₃R₄, —NH—S(O)m-R₃, —NH—CR₃R₄, C(O)—R₅, —C(O)O—R₃,—C(O)NR₃R₄, —S(O)m-, NR₃R₄, nitro, cyano, formyl, acetyl, halogen,—SR^(a), or a protecting group.

International patent application WO 2005/021536 discloses the compoundsof formula

wherein one of the possible B substituents is adamantyl amine.

One of the representative examples is

International patent application WO 2006/012395 discloses the compoundsof formula

as peptidase inhibitors. One of the representative examples is

International patent application WO2005095339 discloses the compounds offormula

as DPPIV inhibitors.

US20050215784 discloses the compounds of formula

as DPPIV inhibitors.

Although there are a few DPPIV inhibitors in different stages ofclinical trials such as the examples given above (LAF-237, MK-0431,BMS-477118, GSK23A), there is still a need for novel compounds in thisarea and the objective of the present invention is to provide novelnor-adamantyl cyano pyrrolidine compounds represented by formula I whichhave a DPPIV inhibitory activity as well as processes for theirpreparation.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide novel compounds offormula I, having serine protease inhibiting activity, particularlydipeptidyl peptidase IV inhibiting activity for lowering blood glucoselevels, lipid levels, cholesterol levels and reducing body weight,against type II diabetes and diabetic complications. The main objectiveof the present invention is therefore, to provide novel nor-adamantylcyano pyrrolidine compounds represented by formula I, their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirbioisosteres, their diastereomers, their polymorphs, theirpharmaceutically acceptable salts, solvates and pharmaceuticallyacceptable compositions containing them.

Another aspect of the present invention is to provide a process for thepreparation of noradamantyl cyano pyrrolidine compounds represented byformula I, their derivatives, their analogs, their tautomeric forms,their stereoisomers, their bioisosters, their diastereomers, theirpolymorphs, their pharmaceutically acceptable salts, and theirpharmaceutically acceptable solvates.

Another aspect of the present invention is to provide novelintermediates, processes for their preparation and use of theseintermediates in processes for the preparation of said noradamantylcyano pyrrolidine compounds represented by formula I and theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their bioisosters, their diastereomers, theirpharmaceutically acceptable salts, and solvates.

Another aspect of the present invention is to provide pharmaceuticalcompositions containing the compounds of the present inventionrepresented by formula I, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their bioisosters, theirdiastereomers, their polymorphs, their salts, solvates, or theirmixtures in combination with suitable carriers, solvents, diluents andother media normally employed in preparing such compositions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is to provide compounds represented by formula I

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their bioisosters, their diastereomers, their polymorphs,their pharmaceutically acceptable salts and their pharmaceuticallyacceptable solvates wherein

-   -   X=CH₂, CHF, CF₂, CHCl, CHOH, CHOCH₃, NH, NCOCH₃, CHPh, O, or S,    -   Y=CN,    -   R₁ and R₅ are selected from hydrogen, C₁-C₄ alkyl, and hydroxy,    -   R₂ is selected from hydrogen, C₁-C₄ alkyl, substituted alkyl,        C₁₋₄ alkoxy C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, R₅NHC₁₋₄ alkyl, and        R₅NHC(NH)NHC₁₋₄ alkyl,    -   R₃ is selected from hydrogen and C₁-C₄ alkyl,    -   R₄ is selected from hydrogen, C₁-C₄ alkyl, substituted alkyl,        C₁-C₄ alkoxy, C₁-C₄ alkanoyloxy, hydroxy, amino, nitro, C₂-C₆        alkenyl, acyl, and halogen,    -   n=1 or 2,    -   m=0, 1, or 2,    -   R=R₁₁, R₁₂, or R₁₃, in which

R₁₁ comprises at least one of the groups selected from a), b), or c),whereupon the optionally substituted cycloalkyl, heterocyclyl, andheteroaryl groups are linked to the noradamantyl moiety either directlyor via a methylene or ethylene adjacent, either by C—C linkage or by C—Nlinkage

a) A cycloalkyl group, which is optionally substituted by C₁-C₄ alkyl,dialkyl, or oxo, preferably a C₄-C₇ ring system, more preferably a C₅-C₆ring system, which may be further functionalized or substituted withmultiple degrees of substitution. Examples of possible cycloalkyl groupsare cyclopentane, cyclohexane, cyclopentane dione, cyclohexane dione andthe possible substitutions include C₁-C₄ alkyl, dialkyl, and oxo.

b) An optionally substituted heteroaryl group, preferably a 5 to 10membered ring system, in which the heteroaryl ring is a monocyclicaromatic ring system or a bicyclic aromatic ring system comprising one,two, or more heteroatoms selected from nitrogen, sulfur, and oxygen.Possible heteroaryl groups include but are not limited to tetrazole,triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole,furan, benzofuran, benzimidazole, indazole, thiophene, andbenzothiophene and the substitutions on the heteroaryl ring may be thesame or different and are selected from R₆ and R₇, wherein R₆ ishydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, hydroxy alkyl,alkylamino, haloalkyl, amino, acyl, COOR₉, or COR₉, and R₇ is selectedfrom a group consisting of hydrogen, hydroxy, halogen, amino, nitro,C₁-C₈ alkyl, C₂-C₄ alkenyl, COOR₉, CONR₈R₉, COR₉, NHCOOR₈, NHS(O)₂R₈,NHS(O)R₈, NHS(O)₂NHR₈, NR₈COOR₉, NR₈COR₉, NR₈S(O)₂R₉, NR₈CONR₈R₉,NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, OSO₂R₈, OCONR₈R₉, SO₂R₈, SOR₈, SR₈,SO₂NR₈R₉, and S(O)₂OR₈. When R₆ and R₇ are present on adjacent carbonatoms of the ring system, they may together form a six membered aromaticring such as phenyl or a heterocyclic ring such as pyridine with furthersubstitutions such as amino, hydroxy, alkyl, alkyl sulfonyl, alkyl thio,alkyl sulfinyl, carboxy, or oxo.

Further preferred heteroaryl groups comprise

these examples do not limit the present invention.

c) A heterocyclyl group optionally substituted by C₁-C₃ alkyl, dialkyland oxo groups, wherein the heterocyclic ring system is a 4- to10-membered mono- or bicyclic ring system with one or more heteroatomsselected from the group consisting of nitrogen, sulfur, and oxygen,wherein the heteroatoms can also be present as functional groups, suchas N-oxides, sulfur oxides, and sulfur dioxides, wherein theheterocyclic ring system may contain one or two double bonds, andwherein the monocyclic heterocyclic ring may be optionally fused to aheteroaryl, aryl, or a cycloalkyl ring optionally substituted with C₁-C₅alkyl, halogens, hydroxy, amino, nitro, haloalkyl, alkylamino, carboxy,NH(CO)R₈, NHS(O)₂R₈, NHC(O)NHR₉, NHSOR₈, NHS(O)₂NHR₈, NR₈COOR₉, NR₈COR₉,NR₈S(O)₂R₉, NR₈CONR₈R₉, NR₈C(S)NR₈R₉, or NHC(O)NHS(O)₂R₈. The possiblesubstitutions of the heterocyclic ring systems include C₁-C₃ alkyl,dialkyl, and oxo groups. Examples of such heterocyclic ring radicalsinclude but are not limited to imidazolidinone,isothiazolidine-1,1-dioxide, pyrrolidine, pyrrolidinedione,oxopyrrolidine, isoxazolidinedione, isoindoledione, morpholine,thiomorpholine, thiomorpholine-1,1-dioxide, thiophene-1,1-dioxide,thiazolidinedione, piperidine, piperazine, tetrahydro pyrimidinone,[1,2]-thiazinane-1,1-dioxide, tetrahydro thiophene-1,1-dioxide,piperidinone, and tetrahydrothiopyran-1,1-dioxide.

Further preferred heterocyclyl groups comprise

wherein R₇ is as described above and Z is CH₂, O, S, SO₂, NH, NR₆, orCH(OH). These examples do not limit the present invention.

R₁₂ is selected from hydrogen, halogen, haloalkyl, hydroxy, carboxy,nitro, amino, cyano, alkyl sulfinyl, alkylsulfonyl, alkylthio, amidinyl,alkoxy, alkoxy carbonylamino, ureido, thiureido, alkanoyl, alkanoyloxy,alkanoyl amino, carbamoyl, guanidyl, optionally substituted C₁-C₈ alkyl,and C₂-C₆ alkenyl.

R₁₃ is optionally substituted aryl, wherein the substituents may be thesame or different and comprises at least one of the groups selected from

a) hydrogen;

b) C₁-C₈ alkyl, C₂-C₆ alkenyl, halo, alkylhalo, alkoxy, alkylsulfonyl,alkylsulfinyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbonylamino,guanidyl, nitro, amino, COOR₉, R₈NHC(O)R₉, COR₉, CONR₈R₉, NHC(O)OR₈,NHC(O)R₈, NHC(O)NR₈R₉, NHC(O)NR₈R₉, NHS(O)₂R₈, NHS(O)R₈, NHS(O)₂NHR₈,NHS(O)₂NHC(O)R₈, NR₈COOR₉, NR₈COR₉, NR₈S(O)₂R₉, NR₈CONR₈R₉,NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, S(O)₂R₈, SOR₈, SR₈, S(O)₂NR₈R₉, OCF₃,OS(O)₂R₈, or OC(O)NR₈R₉.

c) Saturated, partially saturated, or unsaturated, mono- or bicyclicheterocyclic ring system optionally substituted by one or more groupsselected from C₁-C₃ alkyl, C₂-C₆ alkenyl, dialkyl, and oxo, wherein theheterocyclic ring system is a 4- to 10-membered ring with one or moreheteroatoms selected from the group consisting of nitrogen, sulfur, andoxygen, wherein the heteroatoms can also be present as functionalgroups, such as N-oxides, sulfur oxides, and sulfur dioxides. Examplesof such heterocyclic ring radicals include, but are not limited topyridine, pyrimidine, imidazolidinone, imidazolidinethione, indazole,indole, isoindole, quinazoline, quinoline, isoquinoline, cinnalone,isothiazolidine-1,1-dioxide, pyrrolidinone, 2-piperidinone,tetrahydropyrimidinone, azitidinone, and thiazane-1,1-dioxide.

Further preferred heterocyclyl groups comprise

these examples do not limit the present invention.

The R₈, R₉, and R₁₀-groups, which are optionally substituted by halogen,hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy, hydroxyalkyl,amino, alkylthio, or thioalkyl groups, may be the same or different andare individually selected from hydrogen, optionally substituted C₁-C₈alkyl, aryl, arylalkyl, alkoxy carbonyl, and arylalkoxy carbonyl. WhenR₈ and R₉ are present together on a nitrogen atom they may form a 5- or6-membered saturated, partially unsaturated, or unsaturated cyclicsystem containing carbon atoms, at least one nitrogen atom andoptionally one or more other heteroatoms selected from oxygen, sulfur,and nitrogen.

Finally compounds of the invention are either obtained in free form oras a salt thereof, if salt forming groups are present. Compounds of thepresent invention may be converted into pharmaceutically acceptablesalts by reacting them with appropriate acids or bases.

Certain compounds of the present invention of formula I may contain oneor more chiral centers and the present invention incorporates theisolated stereoisomers, their mixtures, as well as the correspondingracemates.

Listed below are definitions of various terms used to describe thisinvention

The term “alkyl” refers to a saturated straight or branched aliphatichydrocarbon chain that optionally may be substituted with multipledegrees of substitution. Examples of “alkyl” include but are not limitedto methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, andisobutyl. The substitutions may be selected from halogens, hydroxy,alkoxy, acyl, amino, and nitro. Unless specified differently, forexample by the phrase “C_(x)-C_(y) alkyl” which refers to an alkyl groupwith specified number of carbons, in the entire specification the term“alkyl group” refers to a C₁-C₈-group. A similar terminology applies toother preferred ranges as well.

The term “alkenyl” used herein, either alone or in combination withother radicals, denotes a straight or branched C₂-C₆ aliphatichydrocarbon chain containing one or more carbon-to-carbon double bondsthat may be optionally substituted with multiple degrees ofsubstitution. The term “alkenyl” includes dienes and trienes of straightand branched chains and include groups such as vinyl, allyl, 2-butenyl,3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl,and 6-heptenyl

The term “acyl” refers to a C(O)R_(a)-group, wherein R_(a) is C₁-C₄straight or branched alkyl or aryl.

The term “acylamino” used herein is represented by a —NHC(O)R_(a)-group,wherein R_(a) is defined as above and examples are CH₃CONH, C₂H₅CONH,C₃H₇CONH, C₆H₅CONH.

The term “alkanoyloxy” refers to a —OC(O)R_(a)-group, wherein R_(a) isC₁-C₄ straight or branched alkyl as defined above; examples areacetyloxy and propanyloxy.

The term “alkanoyl” refers to a —C(O)R_(a)-group, wherein R_(a) is C₁-C₄straight or branched alkyl as defined above; examples are acetyl andpropanoyl.

The term “alkanoylamino” refers to a —NH—C(O)R_(a)-group, wherein R_(a)is C₁-C₄ straight or branched alkyl as defined above; examples areCH₃CONH— and C₂H₅CONH—.

The term “alkoxy” refers to a —OR_(a)-group, wherein R_(a) is alkyl asdefined herein. Representative examples include but are not limited tomethoxy and ethoxy.

The term “alkoxycarbonyl” refers to a —C(O)OR_(a)-group, wherein R_(a)is alkyl as defined herein.

The term “Alkoxycarbonylamino” refers to a —NHC(O)OR_(a)-group whereR_(a) is alkyl as defined herein.

The term “alkylamino” refers to a —N(R_(a))₂-group, wherein one R_(a) isalkyl and the other R_(a) is independently H or alkyl as defined herein.

The term “alkyl sulfinyl” refers to a —S(O)R_(a)-group, wherein R_(a) isalkyl as defined herein.

The term “alkyl sulfonyl” refers to a —S(O)₂R_(a)-group, wherein R_(a)is alkyl as defined herein

The term “alkylthio” refer to a —SR_(a)-group, wherein R_(a) is alkyl asdefined herein. Representative examples include but are not limited to—S—CH₃, —S—CH₂CH₃.

The term “alkylhalo” refers to a R_(a)X-group, wherein R_(a) is alkyl asdefined above and X represents a halogen atom selected from fluorine,chlorine, bromine, and iodine.

The term “Halogen” refers to fluorine, chlorine, bromine, or iodine.

The term “hydroxyalkyl” refers to a R_(a)OH-group, wherein R_(a) isalkyl as defined herein and representative examples include but are notlimited to hydroxy methyl, hydroxy ethyl, and hydroxy propyl.

The term “aryl” refers to an aromatic ring system with five to tencarbon atoms, which may be monocyclic or bicyclic and unsaturated orpartially saturated, and one or more carbons may optionally be replacedby one or more heteroatoms selected from N, O, and S. The term “aryl”includes ring(s) optionally substituted with multiple degrees ofsubstitution and the substitutions may include alkyl, alkylene, Dialkyl,and oxo.

The term “aralkyl” refers to a Ar—R_(a)-group, wherein Ar and R_(a) areas defined above.

The term “arylalkoxycarbonyl” refers to a —C(O)OR_(a)Ar-group, whereinAr and R_(a) are as defined above.

The term “heteroaryl” refers to a monocyclic aromatic ring system or afused bicyclic aromatic ring system comprising two or more aromaticrings, preferably two rings. These heteroaryl rings contain one or moreheteroatom, such as nitrogen, sulfur, and oxygen, wherein functionalgroups, such as N-oxides, sulfur oxides, and dioxides are permissible asheteroatom substitutions. The term “heteroaryl” includes optionallysubstituted ring systems. Examples of heteroaryl groups include furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, indazole, and substituted versions thereof.

The term “heterocyclyl” refers to a 3 to 15 membered ring that is eithersaturated or has one or more double bonds. These heterocyclic ringscontain one or more heteroatoms such as nitrogen, sulfur, and/or oxygenatoms, wherein functional groups such as N-oxides, sulfur oxides, anddioxides are permissible heteroatom substitutions. Such ring may beoptionally fused to one or more other heterocyclic ring(s), aryl ring(s)or cycloalkyl ring(s).

The term “stereoisomers” refers to certain compounds described hereinthat contain one or more chiral centres or may otherwise be capable ofexisting as multiple stereoisomers. Scope of the present inventionincludes pure stereoisomers, mixtures of stereoisomers such as purifiedenantiomers/diastereomers or enantiomerically/diastereomericallyenriched mixtures, and racemates.

The term “bioisosteres” refers to compounds or groups that possess nearmolecular shapes and volumes, approximately the same distribution ofelectrons and which exhibit similar physical properties such ashydrophobicity. Bioisosteric compounds affect the same biochemicallyassociated systems as agonist or antagonists and thereby producebiological properties that are related to each other.

The term “pharmaceutically acceptable salts” includes salts derived frominorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, and Mn, saltsof organic bases such as N,N′-diacetylethylenediamine,2-dimethylaminoethanol, isopropylamine, morpholine, piperazine,piperidine, procaine, diethylamine, triethylamine, trimethylamine,tripropylamine, tromethamine, adamantyl amine, diethanolamine,ethylenediamine, N,N-benzyl phenylethylamine, choline hydroxide,dicyclohexylamine, metformin, benzylamine, phenylethylamine,dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine,purine, pyrimidine, and spermidine, chiral bases like alkylphenylamine,glycinol, and phenyl glycinol, salts of natural amino acids such asglycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine,cysteine, cystine, methionine, proline, hydroxy proline, histidine,ornithine, lysine, arginine, serine, threonine, and phenylalanine,unnatural amino acids such as D-isomers or substituted amino acids,salts of acidic amino acids such as aspartic acid and glutamic acid,guanidine, substituted guanidine wherein the substituents are selectedfrom nitro, amino, alkyl, alkenyl, alkynyl, ammonium, or substitutedammonium salts. Salts may include acid addition salts such as sulphates,nitrates, phosphates, perchlorates, borates, hydrohalides selected fromHCl, HBr, HI, acetates, tartrates, maleates, citrates, succinates,palmoates, methanesulfonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,and ketoglutarates.

The term “pharmaceutically acceptable solvates” refers adducts andco-crystallates, such as hydrates or solvates comprising other solvents,e.g. alcohols.

The term “compounds of the invention” or “present invention” refers tothe compounds of the present invention represented by formula I asdefined herein, their derivatives, their analogs, their tautomericforms, their stereoisomers, their bioisosters, their diastereomers,their polymorphs, as well as their pharmaceutically acceptable salts andsolvates.

The term “suitable pharmaceutically acceptable carriers” include solidfillers or diluents and sterile aqueous or organic solutions. The activeingredient will be present in such pharmaceutical compositions inamounts sufficient to provide the desired effect as described above.Thus, for oral administration, the compounds can be combined with asuitable solid, liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions etc. The pharmaceuticalcompositions may contain additional components such as flavourants,sweeteners, and excipients.

Preferred compounds of the present invention are represented by formulaIa and the generic structure given below. Additionally, preferredembodiments are represented by their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their bioisosters, theirdiastereomers, their polymorphs, their pharmaceutically acceptable saltsand their pharmaceutically acceptable solvates.

wherein:

n=1 or 2

m=0, 1, or 2

X=CH₂, CHF, or S

Y=CN

R₃ is independently selected from hydrogen and C₁-C₄ alkyl

R₄ is hydrogen, C₁-C₄ alkyl, substituted alkyl, C₁-C₄ Alkoxy,alkanoyloxy, hydroxy, amino, nitro, C₂-C₆ alkenyl, acyl, or halogen

R is R₁₁, R₁₂ or R₁₃ and R₁₁, R₁₂, R₁₃ are as defined above.

Preferred compounds of the present invention comprise the followingcompounds:

-   (2S)-1-[1H-1,2,4-triazol-1-ylmethyl(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile-   (2S,4S)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S,4R)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (4R)-3-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrile-   (2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   ((2S)-1-{N-[2-(1,2,4-oxadiazol-3-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrile-   (2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)    phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile-   (2S,4R)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile-   (4R)-3-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrile-   (2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)    phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S,4S)-4-fluoro-1-{N-[2-[4-(2-oxopyrrolidin-1-1)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (4R)-3-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrile-   (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   ((2S)-1-{N-[2-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrile-   (2S)-1-[(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile-   (2S)-1-[(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{[(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile-   (2S)-1-{[(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{[(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile-   (2S)-1-{[(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{[(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile-   (2S)-1-{[(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{[(1-aminotricyclo[3.3.1.0^(3,7)]non-3-yl)    amino]acetyl}pyrrolidine-2-carbonitrile hydrochloride salt-   (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile-   (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl) hexahydro-2,5-methanopentalen-3a    (1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl) hexahydro-2,5-methanopentalen-3a    (1H)-yl]glycyl}pyrrolidine-2-carbonitrile hydrochloride salt-   (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a    (1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)    hexahydro-2,5-methanopentalen-3a    (1H)-yl]glycyl}pyrrolidine-2-carbonitrile hydrochloride salt-   (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile-   (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile    hydrochloride salt-   (2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile-   (2S)-1-{N-[2-(4-aminophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

Another aspect of the present invention provides processes for thepreparation of the compounds of general formula I as described above.

wherein

P is H or a protecting group

L is a leaving group selected from the group consisting of halogens,tosylates, mesylates, and triflates

R, R₁, R₂, R₃, R₄, n, m, X, and Y are as described above

Compounds of formula I are prepared by the following steps comprising:

-   -   a. Coupling one equivalent of a compound of formula III with        about 1 to 5 equivalents of an amine compound of formula II in        its free form or as a salt or as a compound, wherein the amine        is protected, in the presence of one or more bases, such as but        are not limited to alkali metal hydrides like NaH and KH;        organolithiums such as CH₃Li and BuLi; alkoxides like NaOMe,        NaOEt, and KOtBu; tertiary amines like triethylamine and DBU;        carbonates like potassium carbonate, potassium bicarbonate,        sodium carbonate, and cesium carbonate.    -   b. Said coupling is carried at a temperature ranging from about        −5° C. to about 120° C. in an inert solvent such as        dichloromethane, dimethyl formamide, tetrahydrofuran,        acetonitrile, DMSO etc.    -   c. Said coupling is carried for 0.5 to 72 hours, preferably for        0.5 to 60 hours.    -   d. Isolating the resulting compound of formula I.

The compounds of formula III can be prepared by methods found in thestate of the art (WO 2003/002553, WO 00/034241, WO 98/19998, US2005/0038020, Bioorganic and Medicinal Chemistry Letters 1996, 6,1163-66, Journal of Medicinal Chemistry 2003, 46, 2774-2789)

Intermediate II can be obtained via a reaction sequence which issummarized in schemes II and III.

Scheme II is described in the following steps comprising:

1a. Friedel Crafts reaction of benzene with 5-hydroxy adamantanone inpresence of triflic acid over a period of about 1-4 h at refluxtemperature to obtain 5-phenyl adamantan one.

1b. Ring contraction of adamantanone to noradamantanone takes place in 2steps first by converting to 2-methyl-5-phenyl adamantan-2-ol byGrignard reaction, wherein the Grignard reagent is selected from thegroup comprising methyl metal halides like CH₃MgCl, CH₃MgBr, CH₃MgIfollowed by ring contraction in presence of an oxidizing agent insolvents like water, THF, benzene, or a combination of the said solventsfollowed by treatment with a base in a protic solvent such as water,alcohols to form Ib. Preferred alcohols are C₁-C₄ alcohols and the baseis selected from alkalis like NaOH and KOH. The oxidising agent may beselected from chlorine monoxide, hypochlorites like NaOCl or leadtetraacetate in the presence of iodine.

II. The phenyl group of compound Ib is converted to a carboxylic acidgroup in the presence of an oxidizing agent like NaIO₄/RuCl₃ at ambienttemperature to form Ic.

III. The carboxylic group of compound Ic is converted to its alkylester, the keto group is protected with an 1,2-diol such as 1,2-ethanediol or an 1,3-diol such as 1,3-propane diol in the presence of organicsolvents like benzene or toluene at their reflux temperature using anacid catalyst such as p-TSA, CSA, and BF₃ etherate. In the next step,the ester is reduced to the alcohol by a reducing agent such as LiAlH₄,NaBH₄, and DIBAL-H in an inert solvent like THF, ether, or mixturesthereof at a temperature of about 0° C. to form Id.

Scheme III is described in the following steps:

Ia. The hydroxy group of Ia, at 5^(th) position is alkylated by analkylating agent like alkyl halides (such as CH₃I, CH₃Br or isopropylbromide) using strong bases such as NaH, KH, or NaOCH₃ to form 5-hydroxyadamantanone; followed by ring contraction.

Ib. 5-alkoxy adamantanone is converted to 5-alkoxy noradamantyl ethanoneby converting it to 2-methyl-5-alkoxy adamantan-2-ol byGrignard-reaction followed by ring contraction of adamantanone tonoradamantane in the presence of an oxidizing agent in a solvent likewater, THF, benzene, or a combination of such solvents followed by thetreatment with a base in a protic solvent such as water, alcohols, ormixtures thereof to form 5-alkoxy noradamantyl ethanone.

IIa. The ethanone group in the compound obtained by step 1 is convertedto a carboxylic acid by treatment with an oxidizing agent likehypobromites, hypochlorites (such as NaOBr, NaOCl), etc. at about 0° C.followed by an amination step.

IIb. Conversion of the acid to an amine-function by treatment with anazide like NaN₃ or nBu₄NN₃ under acidic conditions in the presence ofsolvents like CHCl₃, CH₂Cl₂, CH₃CN at a temperature of about 35 to 50°C. to obtain alkoxy noradamantylamines (1).

IIIa. In another route, the hydroxyl group of compound Ia is benzylatedby reaction with benzylhalides like benzylbromide in a solvent (e.g.,THF, DMF, NMP) at about 0° C. for about 10-18 hrs to form benzyloxyadamantanone followed by ring contraction to form benzyloxy noradamantylethanone.

IV. The benzyloxy noradamantyl ethanone obtained in step III isconverted to the corresponding acid by an oxidizing agent followed by anamination step (b). The amine thus formed is protected by conventionalamine protecting groups like Boc, Cbz or Fmoc followed by debenzylation(d). The debenzylation is carried out in a H₂ atmosphere underPd/C-catalysis in protic solvents like methanol, ethanol or IPA at roomtemperature for 1-3 hrs to form hydroxy noradamantyl amine, wherein theamine group is protected.

V. Halogenation of the hydroxyl group followed by deprotection of theamine of the compound obtained from step IVd yields a halosubstitutednoradamantylamine in salt form 2.

VI. Deprotection of the amine of the compound obtained from IVd stepyields a hydroxy-substituted noradamantylamine in salt form 3.

Thus obtained intermediate compounds 1, 2, 3 are reacted withchloroacetylcyano pyrrolidines to form the corresponding final compoundsaccording to Scheme I

Scheme IV is described by the following

Ia. The phenyl group of compound Ib (as obtained in scheme I) isnitrated by a nitrating mixture in a conventional procedure byHNO₃/H₂SO₄ at about 0° C.

Ib. The nitrophenyl noradamantyl ethanone obtained in step Ia isoxidized to convert the ethanone to the corresponding acid by anoxidizing agent followed by an amination step.

Ic. The conversion of the acid to the amine is carried out by treatmentwith an azide like NaN₃ or n-Bu₄NN₃ under acidic conditions in thepresence of solvents like CHCl₃, CH₂Cl₂, or acetonitrile at atemperature of about 35 to 50° C.

IIa. The amine group in the compound obtained from step I is protectedby a conventional amine protecting group like Boc, Cbz, or Fmoc.

IIb. The nitro group is reduced to an amine by reducing agents such asPd/C, Pd(OAc)₂, Zn/ammonium formate, or Fe/NH₄Cl etc. in the presence ofsolvents like esters (e.g., ethyl acetate), alcohols (e.g., methanol,ethanol), THF, water or a combination thereof to form the phenyl aminocompound (4).

III. The phenyl amino compound (4) obtained by step II is reacted withX¹(CH₂)_(n)Y¹X¹, wherein X¹ is a halo group selected from F, Cl, Br, I,Y¹ is SO₂ or CO, in the presence of an organic base like triethylamineor DBU and an inert solvent like THF, CH₂Cl₂, acetonitrile, or DMFfollowed by cyclization in the presence of alkali metal hydroxides suchas LiOH, NaOH, or KOH in water with phase transfer catalyst such astetraalkylammonium halides (e.g., tetrabutyl ammoniumiodide) anddeprotection of the amine protecting group to get the correspondingheterocycle substituted phenyl noradamantyl amine compound (5).

IV. In another method compound (2) obtained from step II is reacted withX₁(CH₂)NCO in the presence of organic bases like triethylamine or DBU, asolvent like THF, CH₂Cl₂, acetonitrile, DMF, or mixtures thereof;followed by cyclization to obtain the corresponding heterocyclesubstituted compound, which, by further amine deprotection, form thecorresponding heterocycle substituted phenyl noradamantyl aminecompounds (6).

V. In another method, the phenyl amino compound (2) obtained from stepII is reacted with 2,5-dimethoxy tetrahydrofuran in glacial acetic acidat reflux temperature to form pyrrole substituted compounds, which, onfurther amine deprotection, form the corresponding pyrrole substitutedphenyl noradamantyl amine compounds (7).

VIa. The ethanone group of the phenylnoradamantylethanone (Ib) (asobtained in scheme II) is converted to an acid-group by an oxidizingagent followed by an amination step.

VIb. Conversion of acid to amine by azides as described above, form thecorresponding phenyl substituted noradamantylamine compounds (8).

The obtained intermediate amine compounds 4, 5, 6, 7, 8 are reacted withchloroacetylcyano pyrrolidines to form the corresponding final compoundsaccording to Scheme I.

Scheme V is described by the following:

Ia. The carboxylic acid group of compound Ic (obtained via scheme II) isconverted to the amine by treatment with an azide like NaN₃ in an acidicmedium or with diphenylphosphorylazide in the presence of organic baseslike triethylamine, solvents like benzene or toluene at refluxtemperature.

IIb. The amine group of compound If obtained from step I, is protectedwith a conventional amine protecting group like Boc, Cbz, or Fmoc,followed by an oxidation step.

IIIc. The oxidation of the compound obtained by step II is carried outby oxidizing agents to obtain a carboxylic acid derivative.

IIId. This carboxylic acid group of the compound obtained from step Mcis converted to an amine by azide-treatment with e.g. NaN₃ in an acidicmedium or with diphenylphosphorylazide in the presence of organic baseslike triethylamine, in a solvent like benzene or toluene at refluxtemperature followed by hydrolysis with a metal hydroxide such as KOH,NaOH, LiOH in water at room temperature to form the corresponding aminesubstituted noradamantylamine (9).

IV. The amino compound (If) obtained from step I is reacted withX¹(CH₂)_(n)Y¹X¹, wherein X¹ is halogen and Y¹ is —SO₂— or —CO— in thepresence of organic bases like triethylamine and a solvent like THF orCH₂Cl₂ followed by cyclization using alkalimetal hydroxides in waterwith a phase transfer catalyst such as tetrabutylammonium iodide to getthe corresponding heterocycle substituted compounds with an ethanonegroup, which, after oxidation and amination steps as described in IIIcand IIId, is converted to the corresponding heterocycle substitutednoradamantylamines (10).

The obtained amine intermediate compounds 9, 10 are reacted withchloroacetylcyano pyrrolidines to form the corresponding final compoundsaccording to Scheme I.

Scheme VI is described by the following:

I. To yield compound Ie, the hydroxyl group of compound Id istransformed into a leaving group L by e.g. messylation, tosylation, orhalogenation in the presence of an organic base like triethylamine,N,N-diisopropyl-ethylamine, pyridine, NMP, or N-methylmorpholine at atemperature of about 0° C.

II. The leaving group L of Ie is replaced by R¹¹ group in the presenceof a base and a solvent at a temperature of about 80-120° C. to form Ii.The bases are selected from alkali carbonates or bicarbonates likeNa₂CO₃, NaHCO₃, K₂CO₃, or KHCO₃. The solvents are selected fromdimethylformamide, DMSO, NMP, or similar.

IIIa. The protected keto group of compound II obtained from step II isdeprotected by, e.g., reaction with p-TSA in acetone at refluxtemperature to form an ethanone compound. IIIb. The ethanone compound isoxidized to the corresponding carboxylic acid in the presence of anoxidizing agent, which may be selected from chlorine monoxide,hypochlorites like NaOCl or lead tetraacetate in the presence of iodine.

IIIc. The carboxylic acid is converted to an amine by reaction with anazide like NaN₃ under acidic conditions in the presence of solvents likeCHCl₃, CH₂Cl₂, or acetonitrile at about 35 to 45° C. to form the R¹¹substituted noradamantylamine (11).

IV. In another route, the hydroxyl group of Id as obtained from schemeII, is benzylated by reaction with benzylhalides like benzylbromide insolvents like THF, DMF, or NMP at about 0° C. for about 10-18 hrs toform the keto protected benzyloxy noradamantane (Ig).

Va. The protected keto group of compound Ig is deprotected to obtain theethanone as described in step IIIa.

Vb. The ethanone group of the benzyloxy noradamantylethanone compound isoxidized to yield the carboxylic acid as described in step IIIb.

Vc. The carboxylic group of the compound obtained from step Vb isconverted to an amine by reaction with diphenylphosphorylazide in thepresence of organic bases like triethylamine, solvents like benzene, ortoluene at reflux temperature followed by hydrolysis with metalhydroxides such as KOH, NaOH, or LiOH in water at room temperature toform benzyloxy noradamantylamine (Ih).

VIa. The amine group of the compound Ih obtained from step Vc isprotected by conventional amine protecting groups as described earlierfollowed by a debenzylation step.

VIb. The debenzylation is carried out in the presence of H₂ atmosphereover Pd/C in protic solvents like methanol, ethanol, or IPA at roomtemperature for 1-3 hrs to form compound Ij.

VIIa. The hydroxyl group of compound Ij is mesylated, tosylated, orhalogenated to form a leaving group in the presence of organic baseslike triethylamine, N,N-diisopropyl ethylamine, pyridine,N-methyl-piperidine, or N-methyl-morpholine at ambient temperature.

VIIb. The compound obtained from VIIa is reacted with a R¹¹ group in thepresence of a base and a solvent at a temperature range of about 80-120°C. The bases are selected from alkali carbonates or bicarbonates likeNa₂CO₃, NaHCO₃, K₂CO₃, and KHCO₃. Solvents are selected from DMF, DMSO,NMP etc.

VIIc. The protected amine group of the R¹¹ substituted compound obtainedfrom step VIIb is deprotected by conventional methods, e.g. by treatmentwith dry HCl in solvents like EtOAc, ether, or 1,4-dioxane at atemperature between 0° C. and room temperature to form a R¹¹-substitutednoradamantylamine as hydrochloride salt (12).

VIIIa. In another method, the hydroxyl group of Ij is reacted with theR¹¹ group in the presence of triphenylphosphine,diisopropylazodicarboxylate, and an organic solvent like benzene,toluene, or THF at a temperature from about 20° C. to about 110° C. forabout 2-6 hours to form the R¹¹-substituted compound.

VIIIb. The protected amine group of the R¹¹-substituted compoundobtained from step VIIIa is deprotected by treatment withtrifluoroacetic acid in a solvent like CH₂Cl₂ or CHCl₃ at about 0° C. toform the R¹¹-substituted noradamantanamine as a TFA salt (13).

The obtained intermediate compounds 11, 12, 13 are reacted withchloroacetylcyano pyrrolidines to form the corresponding final compoundsaccording to Scheme I.

Scheme VII is described by the following:

Ia. To form a leaving group L, the hydroxy group of compound Ij ismesylated, tosylated, or halogenated in the presence of organic baseslike triethylamine, N,N-diisopropyl ethylamine, pyridine,N-methyl-piperidine, or N-methyl-morpholine at an ambient temperature.The compound obtained from Ia is reacted with a cyanating agent likeNaCN in the presence of an aprotic solvent like DMF at 100-110° C. forabout 12-15 hrs to obtain a compound (Ik).

IIa. Compound Ik is reacted with hydroxylamine hydrochloride to formamidoxime, which upon reaction with trimethylorthoformate in thepresence of a catalytic amount of camphor sulfonic acid. Finaldeprotection yields compound 14.

The obtained intermediate compound 14 is reacted with chloroacetylcyanopyrrolidines to form the corresponding final compounds according toScheme I.

It is understood that in any of the above schemes any reactive group inthe substrate molecule may be protected according to any conventionalprocedure known in the prior art.

Suitable protecting groups comprise tertiarybutyldimethylsilyl,methoxymethyl, triphenyl methyl, benzyloxycarbonyl, THP etc. for theprotection of hydroxyl or phenolic hydroxy groups; N-Boc, N-Cbz, N-Fmoc,and benzophenoneimine for the protection of amino or anilino groups;acetal protection for aldehydes, ketal protection for ketones. Themethods for the formation and removal of such protecting groups dependon the molecule to be protected which are known in the art.

Also as part of the invention, in carrying out the invention whereverthere is a leaving group it may be selected from the group comprisinghalogens (like chlorine, bromine), o-toluene sulphonyl, o-methylsulphonyl.

The stereoisomers of the compounds according to this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, or lactic acid wherever applicableor chiral bases such as brucine, cinchona alkaloids, or theirderivatives.

The pharmaceutically acceptable salts can be prepared by reacting thecompound of formula I with about 1 to 5 equivalents of bases such asalkalimetal hydroxides, alkalimetal alkoxides, calcium hydroxide, ormagnesium hydroxide in protic or aprotic solvents like methanol,ethanol, propanol, IPA, ether, THF, dioxane etc. Alternatively, whereverapplicable acid addition salts are prepared by treatment with acids suchas hydrohalic acids like HCl, HBr; nitric acid, sulfuric acid,phosphoric acid, p-toluene sulphonic acid, methane sulphonic acid,acetic acid, or citric acid in solvents comprising at least one selectedfrom ethyl acetate, ethers, alcohols, acetone, THF, dioxane, or mixturesthereof.

Different polymorphs of a compound of general formula I of the presentinvention may be prepared by crystallization of the compound of formulaI under different conditions. For example making use of commonly usedsolvents or their mixtures for recrystallization, crystallization atdifferent temperature ranges, different cooling techniques like veryfast to very slow cooling during crystallization, by exposing thecompound to ambient temperature, by heating or melting it followed bygradual cooling etc. The presence of polymorphs may be determined by oneor more methods like solid probe NMR spectroscopy, DSC, TGA, PowderX-Ray diffraction or IR.

In another embodiment of the present invention, the compounds may bepurified by using techniques such as crystallization from solvents suchas pentane, diethylether, isopropyl ether, chloroform, dichloromethane,ethylacetate, acetone, methanol, ethanol, isopropanol, water, or theircombinations, or compound I may be purified by column chromatographyusing alumina or silica gel and eluting the column with solvents such ashexane, petroleum ether, dichloromethane, chloroform, ethylacetate,acetone, methanol, or combinations thereof.

The present invention also provides pharmaceutical compositionscontaining the compounds as defined above, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their bioisosters,their polymorphs, their enantiomers, their diastereomers, theirpharmaceutically acceptable salts, or their pharmaceutically acceptablesolvates in combination with suitable pharmaceutically acceptablecarriers or diluents. The pharmaceutical compositions according to thepresent invention are useful as antidiabetics, hypolipidemics andantihypercholesterolemics.

Suitable pharmaceutically acceptable carriers include solid fillers,diluents, and sterile aqueous or organic solutions. The activeingredient will be present in such pharmaceutical compositions inamounts sufficient to provide the desired effect as described above.Thus, for oral administration, the compounds can be combined with asuitable solid or liquid carrier or a diluent to form e.g. capsules,tablets, powders, syrups, solutions, or suspensions. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavourants, sweeteners, or excipients.

The route of administration may be oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal, or parenteral e.g. rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal, asan ophthalmic solution or an ointment, which effectively transports theactive compound of the present invention which inhibits the DPPIVenzymatic activity to the appropriate or desired site of action. Fororal administration, if a solid carrier is used, the preparation may bein form of tablet, or may be placed in a hard gelatin capsule in powderor pellet form, or it can be in form of a troche or a lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule, or a sterile injectable liquid such asan aqueous or non aqueous liquid suspension or solution. For nasaladministration a liquid carrier, in particular an aqueous carrier, isused as an aerosol application. For parenteral application, suitablecompositions are injectable solutions or suspensions, preferably aqueoussolutions.

A further aspect of the present invention is the use of compounds of theinvention as a pharmaceutical composition in a therapeutically effectiveamount for the treatment of metabolic disorders, blood glucose lowering,for the treatment of type II diabetes, for the treatment of impairedglucose tolerance, for the treatment of impaired fasting glucose, forthe treatment of obesity, for the prevention of hyperglycemia, for thetreatment of dislipidemia, hypercholesteromia, and hypolipidemia.

The compounds of the present invention are effective over a wide dosagerange. For example in the treatment of humans, dosages may be about 0.05to 1000 mg, and preferably about 0.1 to 500 mg per day. The exact dosagedepends on the mode of administration, on the therapy required, the formin which the active ingredient is administered and the patient to betreated; the body weight of the subject to be treated and the preferenceand experience of the physician in charge. Here, the subject isconsidered as a human being.

The invention also encompasses prodrugs of compounds of the invention,which on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of compounds of theinvention, which are readily convertible in vivo into compounds of theinvention.

The invention also encompasses the active metabolites of the compoundsof the present invention.

Assay of Dipeptidyl Peptidase IV Activity

The inhibition of proteolytic activity of DPP-IV was assayed byfollowing the hydrolysis of Ala-Pro-7-amino-4-trifluoromethylcoumarin(Ala-Pro-AFC) and fluorometric quantitation of the liberated AFC. Humanrecombinant DPP-IV (expressed in insect Sf9 cells) was used for theassay. Test compounds were dissolved in dimethyl sulfoxide (DMSO).Generally, the enzyme (about 20 ng/ml in 100 mM Tris-HCl buffer, pH 8.0)was preincubated in the absence (1% DMSO) and presence of variousconcentrations of the test compounds for 15 min at 37° C. The reactionwas initiated by the addition of 20 μM Ala-Pro-AFC and further incubatedfor 30 min at 37° C. The AFC liberated was measured in aspectrofluorometer with excitation and emission wavelengths set at 400nm and 510 nm, respectively. Results are expressed as percent inhibitionof enzyme activity. A reference standard (a known inhibitor of DPP-IV)was always included in the assay.

The compounds of the present invention were found to inhibit DPPIVinduced fluorescence with inhibitory constants in a range of about 0.5nM to 500 nM. In a preferred range, the compounds of the presentinvention inhibited DPPIV induced fluorescence with inhibitory constantsof about 0.1 nM to 300 nM and in a more preferred range the compounds ofthe present invention inhibited DPPIV induced fluorescence withinhibitory constants of about 1 nM to 120 nM.

As shown in the Table below, the examples exerted potent inhibition ofDPP-IV.

IC₅₀ value Compound in nM Example 1 8.1 Example 2 2.8 Example 3 >300Example 4 7 Example 5 11 Example 6 100 Example 7 30 Example 8 22 Example9 31.2 Example 10 ~30 Example 11 20 Example 12 5 Example 13 300 Example14 6.4 Example 15 4 Example 16 0.95 Example 17 8.7 Example 18 ~30Example 19 15.4 Example 20 30 Example 21 64.5 Example 22 30 Example 2311.9 Example 24 100 Example 25 100 Example 26 21.8 Example 27 30 Example28 30 Example 29 ~30 Example 30 ~32.4 Example 31 21.0 Example 32 53.6

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention butdo not limit the scope of the invention.

Preparation I 1-(1-Phenyltricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone

Step I: Adamantanone (12 g, 80 mmol) was added under stirring to nitricacid (98%, 100 mL) at ice bath temperature over a period of 15 minutes.The reaction mixture was stirred at room temperature for 72 h and thenheated to 60° C., for 2 h until most of the nitrogen dioxide evaporated.Excess nitric acid was distilled off under reduced pressure. The lightyellow oil solidified upon cooling (NO₃ adduct of the hydroxyketone).Water (40 mL) and conc. H₂SO₄ (98%, 15 mL) were added. The resultingclear yellow solution was heated on the steam bath in a hood (nitrousfumes) for 1 h. The solution was then cooled and extracted with a 2:1mixture of n-hexane and diethylether to remove unreacted adamantanone(1.0 g). The acid layer was neutralized with 30% aq. NaOH solution, andwhile warm, extracted with chloroform. The extracts were combined,washed with brine solution, and concentrated in vacuum. The crudeproduct was dissolved in CH₂Cl₂ (15 mL) and hexane was added until nomore precipitate was formed. The solid material was isolated byfiltration and dried to get 5-hydroxy-adamantan-2-one. Yield: 9.0 g(70%). Solid; M.R: 278.8-300° C. (decomposes) m/z (M+1) 167; ¹H NMR(CDCl₃) 300 MHz δ 2.70-2.55 (m, 2H), 2.36-2.32 (m, 1H), 2.11-1.93 (m,10H). ¹³C NMR (CDCl₃) 75 MHz δ 217.0, 66.7, 46.7, 46.6, 44.7 (2C), 43.8,37.9 (2C), 29.5.

Step II: To a stirred solution of compound 5-hydroxyadamantan-2-one(10.0 g, 60.2 mmol) in benzene (180 mL) was addedtrifluoromethanesulfonic acid (5.3 mL, 60.2 mmol) over a period of 30minutes at r.t. After stirring the reaction mixture for 5 minutes atr.t, it was refluxed for 4 h. The reaction mixture was cooled to 0° C.and sat. aq. NaHCO₃ (76 mL) was added over a period of 30 minutes. Twolayers were separated, the aqueous layer was extracted with ether andthe combined layer was washed with water and brine, dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to obtain5-Phenyladamantan-2-one (10.5 g) as a white solid in 80% yield. M.R:53.8-60.9° C. m/z (M+1) 227; IR (cm⁻¹): 2921, 2853, 1717, 1446, 1060,758, 698. ¹H NMR (CDCl₃) 300 MHz δ 7.37-7.30 (m, 4H), 7.26-7.19 (m, 1H),2.70-2.63 (m, 2H), 2.30-2.0 (m, 11H). ¹³C NMR (CDCl₃) 75 MHz δ 217.8,147.8, 128.3 (2C), 126.1, 124.6 (2C), 46.9 (2C), 44.3 (2C), 41.9, 35.9,38.4 (2C), 28.0.

Step III: Freshly prepared methylmagnesium iodide in ether (1 M, 85 mL),was added through a canola to 5-phenyladamantan-2-one (9.6 g, 42.5 mmol)obtained in step II, in THF (85 mL) at 0° C. After stirring at 0° C. for0.5 h, the reaction mixture was quenched by adding sat. aq. NH₄Clsolution. The organic layer was separated and the aqueous layer wasextracted with diisopropylether. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄, and the solvent wasremoved under reduced pressure to obtain2-methyl-5-phenyl-adamantan-2-ol (9.9 g) as an off-white solid in 97%yield. M.R: 98-100.4° C. m/z (M+23) 265; ¹H NMR (CDCl₃) 300 MHz δ7.42-7.28 (m, 4H), 7.24-7.18 (m, 1H), 2.47-2.26 (m, 2H), 2.14-2.09 (m,3H), 1.96-1.70 (m, 6H), 1.61-1.57 (m, 2H), 1.42 (s, 3H). ¹³C NMR (CDCl₃)75 MHz δ 150.0, 128.1 (2C), 125.7, 124.8 (2C), 73.3, 44.0 (2C), 40.5(2C), 39.6 (2C), 35.9, 32.0, 27.6.

Step IV: 2-Methyl-5-phenyl-adamantan-2-ol (20 g, 82.6 mmol) obtained instep III, (86 g, 355.4 mmol), dissolved in a mixture of AcOH (76.3 mL)and THF (360 mL) was added dropwise via an addition funnel to the icebath cooled NaOCl (4%, 3.5 L) solution over a period of 15 minutes.Solid n-Bu₄NI (13.1 g, 35.6 mmol) was added and the reaction mixture wasstirred for 1.5 h. The two layers were separated, the aqueous layer wasextracted with diisopropylether and the combined organic layer waswashed with water and brine, dried over Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was dissolved in methanol(165 mL), KOH (39.8 g, 300 mmol) was added, and the mixture was refluxedfor 1 h. The solvent was evaporated under reduced pressure and the crudeproduct was purified by column chromatography to yield compound1-(1-phenyltricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone (50.0 g) in 59%yield as viscous liquid. m/z (M+1) 241; IR (cm⁻¹): 2924, 2867, 1697,1445, 1356, 1223, 757, 699. ¹H NMR (CDCl₃) 300 MHz δ 7.38-7.19 (m, 5H),2.86-2.80 (m, 1H), 2.59-2.50 (m, 1H), 2.32-2.25 (m, 1H), 2.23 (s, 3H),2.10-1.99 (m, 4H), 1.90-1.79 (m, 4H), 1.78-1.71 (m, 1H). ¹³C NMR (CDCl₃)75 MHz δ, 211.7, 146.7, 128.2 (2C), 125.7 (2C), 124.7, 61.9, 50.2, 49.0,47.9, 45.7, 42.4, 42.3, 37.6, 26.4.

Preparation 2[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methylmethanesulfonate

Step I: To a stirred mixture of1-(1-Phenyltricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone (8.0 g, 33.3 mmol)as obtained in preparation 1, carbontetrachloride (66 mL), acetonitrile(66 mL) and water (100 mL), cooled to 0° C., was added sodiumperiodate(31.9 g, 149 mmol) and ruthenium (III) chloride hydrate (0.44 g, 1.7mmol). The reaction mixture was gradually warmed to ambient temperatureand stirred for 2 h. The reaction mixture was diluted withdiisopropylether (100 mL) and stirred for 15 minutes to precipitateblack RuO₂. The reaction mixture was then filtered through a pad ofcelite and the organic layer was extracted with 1N NaOH solution (3×25mL). The organic layer was dried over Na₂SO₄ and the solvent wasevaporated under vacuum to obtain unreacted starting material (3.04 g12.67 mmol). The aqueous layer was acidified with conc. HCl andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, and the solvent was removed under reducedpressure to obtain 3-acetyltricyclo[3.3.1.0^(3,7)]nonane-1-carboxylicacid (4.0 g) as off-white solid in 57% yield. M.R: 90-95.0° C. m/z (M+1)209. IR cm⁻¹ 2935, 1694, 1413, 1357, 974, 746. ¹H NMR (CDCl₃) 300 MHz δ2.77-2.73 (m, 1H), 2.54-2.48 (m, 1H), 2.44-2.34 (m, 1H), 2.20 (s, 3H),2.18-2.09 (m, 1H), 7.38-7.19 (m, 5H), 2.86-2.80 (m, 1H), 2.59-2.50 (m,1H), 2.32-2.25 (m, 1H), 2.23 (s, 3H), 2.18-2.09 (m, 1H), 2.06-1.74 (m,7H), 1.73-1.61 (m, 1H). ¹³C NMR (CDCl₃) 75 MHz δ 211.0, 181.3, 61.5,50.3, 47.9, 45.9, 45.6, 42.6, 41.9, 36.8, 35.6, 26.4.

Step II: To 3-acetyltricyclo[3.3.1.0^(3,7)]nonane-1-carboxylic acid (2.4g, 11.4 mmol) obtained in step I, in MeOH (48 mL) cooled to ice bathtemperature, was added acetyl chloride (1.64 mL, 22.8 mmol). Thereaction mixture was gradually warmed to room temperature and stirredfor 2 h. The volatiles were removed under reduced pressure and the crudeproduct was purified by column chromatography to obtain methyl3-acetyltricyclo[3.3.1.0^(3,7)]nonane-1-carboxylate (2.4 g) in 93% yieldas viscous liquid. m/z (M+1) 223. IR cm⁻¹ 2953, 1728, 1698, 1461, 1234,1078, 755. ¹H NMR (CDCl₃) 300 MHz δ 3.66 (s, 3H), 2.75-2.70 (m, 1H),2.53-2.46 (m, 1H), 2.40-2.32 (m, 1H), 2.19 (s, 3H), 2.15-2.05 (m, 1H),2.03-1.60 (m, 8H). ¹³C NMR (CDCl₃) 75 MHz δ 210.9, 175.3, 61.4, 53.4,51.6, 50.5, 48.0, 45.9, 45.6, 42.6, 41.9, 36.8, 35.9, 26.4.

Step III: A mixture of methyl3-acetyltricyclo[3.3.1.0^(3,7)]nonane-1-carboxylate (2.0 g, 8.9 mmol)obtained in step II, 1,2-ethanediol (8.9 mL), p-TSA (47 mg, 5 mol %) andbenzene (36 mL) was refluxed using a Dean-Stark apparatus for 1 h. Thereaction mixture was cooled to room temperature, 10% aq. NaHCO₃ (36 mL)was added, and the two layers were separated. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, and the solvent was evaporated under reducedpressure to obtain methyl3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]nonane-1-carboxylate(2.2 g) in 93% yield as viscous liquid. m/z (M+1) 267. IR cm⁻¹ 2954,1731, 1698, 1460, 1236, 1046, 752. ¹H NMR (CDCl₃) 300 MHz δ 4.07-3.94(m, 4H), 3.66 (s 3-H), 2.44-2.36 (m 2-H), 2.27-2.18 (m, 1H), 2.12-2.02(m, 1H), 1.94-1.81 (m, 8-H), 1.30 (s, 3H).

Step IV: Methyl3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]nonane-1-carboxylate(2.3 g, 8.64 mmol) obtained in step III, in THF (15 mL) was added slowlyunder N₂ atmosphere through a dropping funnel to a suspension of LiAlH₄(0.32 g, 8.64 mmol) in ether (15 mL) at ice bath temperature. Thereaction mixture was stirred for 30 minutes before being quenched byaddition of sat. aq. NH₄Cl solution (9 mL), followed by 1N NaOH solution(9 mL) and the reaction mixture was stirred at room temperature for 15minutes before it was filtered through a pad of celite. The organiclayer was washed with brine, dried over Na₂SO₄ and the solvent wasevaporated under reduced pressure to obtain[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methanol(1.9 g) in 94% yield as viscous liquid. m/z (M+1) 269; IR cm⁻¹ 3436,2936, 1634, 1459, 1373, 1309, 1047, 757. ¹H NMR (CDCl₃) 300 MHz δ4.15-3.80 (m, 4H), 3.53 (s 3H), 2.50-2.30 (m 2H), 1.90-1.30 (m, 10H),1.29 (s, 3H).

Step V: To a solution of[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methanol(2.0 g, 8.47 mmol) obtained in step IV, in THF (35 mL) at ice bathtemperature, was sequentially added triethylamine (3.5 mL, 25.4 mmol),DMAP (52 mg, 0.42 mmol), and methanesulfonyl chloride (0.97 mL, 12.7mmol). After stirring the reaction mixture at the same temperature for0.5 h, it was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ and the solventwas removed under reduced pressure. The crude product was purified bycolumn chromatography to obtain title compound[3-(2-Methyl-1,3-dioxolan-2-yl) tricyclo[3.3.1.0^(3,7)]non-1-yl]methylmethane sulfonate (2.4 g) in 90% yield as viscous liquid. m/z (M+1) 317.IR cm⁻¹ 2954, 1461, 1356, 1216, 1174, 1048, 756. ¹H NMR (CDCl₃) 300 MHzδ 4.15-3.90 (m, 4H), 3.00 (s 3H), 2.44-2.36 (m 2H), 1.89-1.79 (m, 2H),1.78-1.42 (m, 8H), 1.29 (s, 3H). ¹³C NMR (CDCl₃) 75 MHz δ 112.1, 76.3,64.95, 64.9, 57.3, 46.6, 45.3, 44.9, 44.5, 42.9, 39.8, 36.9, 36.7, 36.3,20.

Preparation 3 {3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl methanesulfonate

Step I: To a suspension of NaH (60% dispersed in nujol, 3.36 g, 21 mmol)in THF (84 mL) cooled to ice bath temperature was added a solution of[3-(2-Methyl-1,3-dioxolan-2-yl)tricycle[3.3.1.0^(3,7)]non-1-yl]methanol(10.0 g, 42.0 mmol) (as obtained in preparation 2 step IV) in THF (84mL) via a syringe over a period of 30 minutes. After stirring thereaction mixture for 30 minutes at room temperature, nBu₄NI (0.37 g, 1.0mmol) was sequentially added; followed by benzylbromide (5.0 mL, 42.0mmol). The reaction mixture was warmed to room temperature and stirredfor 16 h until TLC revealed completion of the reaction. After coolingthe reaction mixture to ice bath temperature, excess NaH was quenched byadding sat. aq NH₄Cl solution. The two layers were separated and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and the solvent wasevaporated under reduced pressure to obtain a crude reaction mass, whichwas purified by column chromatography to yield2-[1-(benzyloxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]-2-methyl-1,3-dioxolane(11.0 g) as viscous liquid in 80% yield. m/z (M+1) 329; ¹H NMR (CDCl₃)300 MHz δ 7.38-7.22 (m, 5H), 4.50 (s, 2H), 4.02-3.92 (m, 4H), 3.24 (s,2H), 2.38-2.30 (m, 2H), 1.88-1.71 (m, 2H), 1.70-1.60 (m, 4H), 1.55-1.39(m, 4H), 1.27 (s, 3H).

Step II: A mixture of2-[1-(benzyloxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]-2-methyl-1,3-dioxolane(2.6 g, 7.9 mmol), p-toluenesulfonic acid (0.3 g, 1.6 mmol), and acetone(31.6 mL) was refluxed for 4 h. The volatiles were removed under vacuumand the residue was diluted with EtOAc, washed with 10% aq. NaHCO₃ andbrine, dried over Na₂SO₄, and the solvent was evaporated under reducedpressure to obtain1-{1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]non-3-yl}ethanone (2.1 g)as a viscous liquid in 93% yield. m/z (M+1) 285; ¹H NMR (CDCl₃) 300 MHzδ 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.27 (s, 2H), 2.70-2.62 (m, 1H),2.47-2.40 (m, 1H), 2.16 (s, 2H), 2.0-1.90 (m, 2H), 1.81-1.56 (m, 7H),1.50 (dd, J=3.0, 11.0 Hz, 1H).

Step III: To a mixture of NaOH (30.6 g, 765 mmol), H₂O (255 mL) and 1,4dioxane (51 mL) at ice bath temperature was added Br₂ (15.2 mL, 285.6mmol) and stirred for 15 minutes. This hypobromite solution was addeddropwise to a stirred solution of1-{1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]non-3-yl}ethanone (14.5g, 51.0 mmol) in 1,4-dioxane (51 mL) at ice bath temperature. Thereaction mixture was gradually warmed to r.t. and stirred for 1 h. Thereaction mixture was cooled to ice bath temperature and quenched byadding AcOH (46.7 mL, 765 mmol). The reaction mixture was diluted withwater, extracted with EtOAc, the combined organic layers were washedwith brine, dried over Na₂SO₄, and the solvent was removed under reducedpressure to obtain1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid(8.0 g) as white solid in 55% yield. m/z (M−1), 285; ¹H NMR (CDCl₃) 300MHz δ 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.27 (s, 2H), 2.70-2.62 (m, 1H),3.47-3.38 (m, 1H), 2.16 (s, 2H), 2.12-1.98 (m, 2H), 1.90-1.55 (m, 7H),1.50 (dd, J=3.0, 11.0 Hz, 1H).

Step IV: To a stirred mixture of1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid(1.8 g, 6.3 mmol) obtained in step III, triethylamine (2.6 mL, 18.9mmol) and toluene (25 mL) at ice bath temperature was addeddiphenylphosphoryl azide (1.5 mL, 6.93 mmol). The reaction mixture waswarmed to r.t, stirred for one hour, and then refluxed for 4 h. Uponcompletion of the reaction, the reaction mixture was transferred to aseparatory funnel and washed with water. The organic layer was stirredwith aq. KOH solution (50% w/v, 12.6 mL), and nBu₄NI (120 mg, 0.32 mmol)for 2 h. The reaction mixture was cooled to ice bath temperature,acidified with 2N KHSO₄ to pH 2, extracted with ether, the aqueous layerwas basified with aq. NaOH solution (50% w/v) and extracted withchloroform. The combined organic layers were dried over anhydrous Na₂SO₄and the solvent was evaporated under reduced pressure to obtain1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amine (0.82 g) asviscous liquid in 51% yield. m/z (M+1) 258; ¹H NMR (CDCl₃) 300 MHz δ7.37-7.24 (m, 5H), 4.50 (s, 2H), 3.24 (s, 2H), 2.37-2.29 (m, 1H),2.0-1.81 (m, 3H), 1.78-1.70 (m, 1H), 1.70-1.45 (m, 7H), 1.40 (dd, J=2.9,10.7 Hz, 1H).

Step V: To a stirred solution of1-[(benzyloxy)methyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amine (0.82 g, 3.2mmol) obtained in step IV in dichloromethane (13 mL) at ice bathtemperature was added Et₃N (0.67 mL, 4.8 mmol) and ditertiarybutyldicarbonate (0.77 g, 3.5 mmol). After stirring the reaction mixtureat room temperature for 1 h, the volatiles were removed under reducedpressure and the crude product was purified by column chromatography toobtain tert-butyl [1-(benzyloxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate as a viscous liquid(1.0 g) in 88% yield. m/z (M+1) 358; ¹H NMR (CDCl₃) 300 MHz δ 7.37-7.24(m, 5H), 4.49 (s, 2H), 3.25 (s, 2H), 2.48-2.38 (m, 1H), 2.37-2.30 (m,1H), 2.10-1.87 (m, 2H), 1.82-1.67 (m, 2H), 1.67-1.39 (m, 6H), 1.44 (s,9H).

Step VI: To a stirred mixture of tert-butyl[1-(benzyloxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate (1.0 g,2.8 mmol) obtained in step V in MeOH (11 mL), Pd/C (10%, 0.2 g) wasadded. The H₂ pressure was then applied with the balloon for 2 h. Thereaction mixture was filtered through a pad of celite and the filtratewas concentrated under reduced pressure to obtain tert-butyl[1-(hydroxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate as a viscousliquid (0.7 g) in 95% yield. m/z (M+1) 268; ¹H NMR (CDCl₃) 300 MHz δ4.74 (s (br), 1H), 3.45 (s, 2H), 2.50-2.40 (m, 1H), 2.40-2.33 (m, 1H),2.05-1.87 (m, 4H), 1.80 (dd, J=2.4, 10.3 Hz, 1H), 1.65 (dd, J=3.0, 10.0Hz, 1H), 1.54-1.40 (m, 3H), 1.45 (s, 9H), 1.37 (dd, J=3.1, 10.0 Hz, 1H).

Step VII: To a stirred solution of tert-butyl[1-(hydroxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate (0.65 g,2.45 mmol) obtained in step VI in THF (10 mL) at ice bath temperature,was sequentially added Et₃N (1.0 mL, 7.35 mmol), DMAP (20 mg, 0.16mmol), and methanesulfonyl chloride (0.29 mL, 3.7 mmol). After stirringthe reaction at the same temperature for 0.5 h, it was diluted withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, and the solvent was removed under reducedpressure. The crude product was purified by column chromatography toobtain title compound {3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl methane sulfonateas a viscous liquid (0.84 g) in 100% yield. m/z (M+1) 358; ¹H NMR(CDCl₃) 300 MHz δ 4.76 (s (br), 1H), 4.02 (s, 2H), 3.01 (s, 2H), 2.99(s, 3H), 2.54-2.44 (m, 1H), 2.42-2.35 (m, 1H), 2.20-1.87 (m, 4H), 1.82(dd, J=2.2, 10.5 Hz, 1H), 1.76-1.58 (m, 4H), 1.57-1.48 (m, 1H), 1.45 (s,9H).

Preparation 4Benzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate

Step I: Nitration mixture (1 mL) [the nitration mixture was prepared bymixing of 10.5 g of nitric acid (d 1.375 at 22° C.), 180.0 g of conc.sulphuric acid (d 1.84 at 22° C.), and 16 g of H₂O) was added drop wiseto a stirred solution of1-(1-phenyltricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone (240 mg, 1.0 mmol)obtained in preparation 1, in nitromethane (4 mL) at 0° C. Afterstirring for 2 h, the reaction mixture was poured into ice cold waterand extracted with EtOAc, the combined organic layers were washed withbrine and dried over Na₂SO₄. The solvent was evaporated under reducedpressure and the crude product was purified by column chromatography toobtain 1-[1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone asan off-white solid (250 mg) in 88% yield. M.R: 61.3-66.6° C. m/z (M+1)286; IR cm⁻¹ 2953, 1697, 1598, 1519, 1217, 1110, 852, 768. ¹H NMR(CDCl₃) 300 MHz δ 8.17 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H),2.87-2.80 (m, 1H), 2.61-2.55 (m, 1H), 2.34-2.26 (m, 1H), 2.23 (s, 3H),2.13-1.98 (m, 4H), 1.90-1.71 (m, 5H).

Step II: To a stirred solution of NaOH (6.3 g, 158.0 mmol), H₂O (54.0mL) and 1,4 dioxane (7 mL) at ice bath temperature was added Br₂ (3.2mL, 59.0 mmol) and stirred for 5 minutes. The formed hypobromitesolution was added dropwise to a stirred solution of1-[1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone (3.0 g,10.53 mmol) obtained in step I, in 1,4-dioxane (14 mL) at ice bathtemperature. The reaction mixture was gradually warmed to r.t. and after1 h, it was cooled to ice bath temperature and acidified with conc. HCl,diluted with water, and extracted with EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure to obtain1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid (2.27g) in 75% yield as off-white solid; M.R: 145-150° C. m/z (M−1) 286; IRcm⁻¹ 3437, 2945, 1693, 1596, 1511, 1408, 1352, 946, 839, 749. ¹H NMR(CDCl₃) 300 MHz δ 8.16 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H),2.96-2.88 (m, 1H), 2.59-2.52 (m, 1H), 2.44-2.33 (m, 1H), 2.23-2.03 (m,4H), 2.02-1.68 (m, 5H).

Step III: To the stirred solution of1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid (3.0 g,10.45 mmol) obtained in step II, in CHCl₃ (21 mL) was added conc. H₂SO₄(4.2 mL, 78.9 mmol) then solid NaN₃ was added in portions, so that thetemperature of the reaction did not rise above 40° C. The reactionmixture was warmed to 45° C. and after stirring for 2 h it was cooledagain to ice bath temperature, diluted with water and extracted withEtOAc. The aqueous layer was basified with 50% NaOH solution andextracted with CHCl₃. The combined organic layer was washed with brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure toobtain 1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine as anoff-white solid (2.0 g) in 74% yield. M.R: 201.0-205.9° C. m/z (M+1)259; IR cm⁻¹ 3435, 2941, 1643, 1596, 1518, 1400, 1349, 1013, 750. ¹H NMR(CDCl₃) 300 MHz δ 8.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H),3.70-3.60 (d (br), 2H), 2.62-2.50 (m, 2H), 2.38-2.23 (m, 3H), 2.15-2.0(m, 3H), 1.95-1.60 (m, 4H).

Step IV: To a stirred mixture of1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine (2.0 g, 8.0 mmol)obtained in step III, K₂CO₃ (3.5 g, 24 mmol) in THF (80 mL), cooled toice-bath temperature was added benzylchloroformate (50% w/v in Toluene,2.2 mL, 12 mmol). After stirring the reaction mixture at r.t for 2 h, itwas diluted with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, and the solvent wasremoved under reduced pressure to obtainbenzyl[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamateas an off-white solid (2.1 g) in 70% yield. M.R: 104.1-105.9° C.; m/z(M+1) 393; IR cm⁻¹ 3440, 2952, 1714, 1518, 1349, 1216, 757; ¹H NMR(CDCl₃) 300 MHz δ 8.12 (d, J=8.8 Hz, 2H), 7.50-7.27 (m, 7H), 5.20-5.0 (s(br), 2H), 2.65-2.55 (m, 1H), 2.50-1.55 (m, 11H). ¹³C NMR (CDCl₃) 75 MHzδ 155.1, 154.2, 146.1, 136.4, 131.1, 128.5 (2C), 128.1 (2C), 126.6 (2C),123.4 (2C), 66.3, 64.4, 49.248.0, 47.5, 43.8, 42.1, 40.8, 37.0.

Step V: To a stirred solution ofbenzyl[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate(1.0 g, 2.55 mmol) as obtained in step IV in a 1:2:4 mixture of water,THF, and ethanol respectively (10 mL) was added solid NH₄Cl (0.5 g, 9.3mmol) and Fe powder (0.5 g, 9.0 mmol). The reaction mixture was heatedto reflux for 2 h. The reaction mixture was cooled to room temperatureand filtered through a small pad of celite. The filtrate was evaporatedunder reduced pressure and the residue was diluted with water andextracted with EtOAc. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and the solvent was evaporated under reducedpressure to obtain benzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate as off-white solid(0.75 g) in 81% yield. m/z (M+1) 363; IR cm⁻¹ 3441, 2950, 1715, 1517,1346, 1216, 756. ¹H NMR (CDCl₃) 300 MHz δ 7.45-7.05 (m, 9H), 5.20-5.0 (s(br), 2H), 2.65-2.50 (m, 1H), 2.50-2.40 (m, 1H), 2.36-1.57 (m, 10H).

Preparation 5(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile

Step I: To a stirred solution of(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) inmethanol (400 mL) cooled to 0° C. was added acetyl chloride (14.3 mL,0.2 mol) over a period of 30 min. The reaction mixture was warmed toroom temperature and stirred for 2 h. The volatiles were removed underreduced pressure and the residue was triturated with ether several timesto get methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloridesalt as a white powder (14.5 g) in 100% yield. m/z (M+1) 145; ¹H NMR(DMSO-d₆) 300 MHz δ 5.7-5.5 (s (br), 1H), 4.55-4.35 (m, 2H), 3.76 (s,3H), 3.35 (d, J=12 Hz 1H), 3.10 (d, J=12 Hz 1H), 2.25-2.0 (m, 2H).

Step II: To a stirred suspension of the hydrochloride salt obtained instep I (14.5 g, 0.1 mol) in CH₂Cl₂ (400 mL) cooled to 0° C. was addedEt₃N (28 mL, 0.2 mol), DMAP (0.61 g, 5 mmol), and Boc anhydride (27.5mL, 0.12 mol). The reaction mixture was gradually warmed to roomtemperature and stirred for 2 h. The solvent was then removed undervacuum and ether was added to the residual solid. The solid was filteredthrough a sintered funnel and washed thoroughly with ether. The filtratewas evaporated under reduced pressure. The residue was dissolved inCH₂Cl₂ and washed with sat. NaCl and sat. NaHCO₃ followed by drying overanhydrous Na₂SO₄. The solvent was evaporated under reduced pressure toobtain light yellow oil which solidified under high vacuum. Theresulting solid was triturated several times with hexanes. The solid wasdried under high vacuum yielding 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate as a white solid (24.5 g)in 100% yield. (M+1) 245; ¹H NMR (CDCl₃) 300 MHz δ 4.54-4.37 (m, 2H),3.75 (s, 3H), 3.70-3.40 (m, 2H), 2.48-2.21 (m, 2H), 2.13-2.0 (m, 1H),1.46 (s, 3H), 1.41 (s, 6H).

Step III: To a stirred solution of compound obtained in step II (24.5 g,0.1 mol) in 1,2-dichloroethane (300 mL) cooled to −10° C. was addeddiethylaminosulfur trifluoride (19.7 mL, 0.15 mol) over a period of 30minutes. The reaction mixture was stirred at this temperature for 1 hthen at room temperature for 16 h. The reaction mixture was quenched byadding mixture of crushed ice (300 g) and solid NaHCO₃ (25.2 g, 0.3mol). The two layers were separated and the aqueous layer was extractedwith dichloromethane. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and the solvent was removed under reducedpressure to obtain 1-tert-butyl 2-methyl(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a viscous liquid (24.7g) in 100% yield. [α]_(D) −53.3, (c, 1.0, CHCl₃). m/z (M+1) 248; ¹H NMR(CDCl₃) 300 MHz δ 5.20 (ddd, J=3.8, 3.8, 49.1 Hz, 1H), 4.55 (d, J=9.5Hz, ½H), 4.42 (d, J=8.9 Hz, ½H), 3.90-3.55 (m, 2H), 3.75 (s, 3H),2.55-2.20 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).

Step IV: To the stirred solution of 1-tert-butyl-2-methyl(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (24.7 g, 0.1 mol) obtainedin step III in THF (200 mL) cooled to 0° C. was added a solution of LiOH(3.6 g, 0.15 mol) in water (200 mL) over a period of 30 min. Thereaction mixture was warmed to room temperature and stirred for 12 huntil the TLC reveals completion of the reaction. The reaction mixturewas diluted with water, ether, and two layers were separated. Theaqueous layer was acidified with conc. HCl and extracted with EtOAc. Thecombined organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, and the solvent was evaporated under reduced pressureto obtain(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid asan off white solid (21 g) in 90% yield. [α]_(D), −65.7 (c, 1.0, CHCl₃);m/z (M−1) 232; ¹H NMR (CDCl₃) 300 MHz δ 5.22 (ddd, J=3.8, 3.8, 52.3 Hz,1H), 4.60-4.40 (m, 1H), 3.95-3.50 (m, 2H), 2.78-2.15 (m, 2H), 1.6-1.35(m, 9H).

Step V: To a stirred solution of acid obtained in step IV (17.3 g, 0.074mol) in acetonitrile (220 mL) at room temperature was added pyridine(6.6 mL, 0.082 mol), Boc anhydride (20 mL, 0.089 mol). After 1 h, solidNH₄HCO₃ (9.4 g, 0.12 mol) was added and the reaction mixture was stirredfor 12 h. The reaction mixture was diluted with EtOAc and washed with amixture (1:1 by v/v) of brine and 1N HCl. The organic layer was driedover anhydrous Na₂SO₄ and the solvent was removed under vacuum to obtaintert-butyl (2S,4S)-2-(aminocarbonyl)-4-fluoropyrrolidine-1-carboxylate(17 g) as a viscous liquid. The product was used for the next reactionwithout further purification. m/z (M+1) 233; ¹H NMR (CDCl₃) 300 MHz δ6.70-6.60 (s (br), ½H), 6.30-6.10 (s (br), ½H), 5.50-5.40 (s (br), 1H),5.22 (ddd, J=3.4, 3.4, 52.0 Hz, 1H), 4.50-4.30 (m, 1H), 3.95-3.50 (m,2H), 2.90-2.10 (m, 2H), 1.48 (s, 9H).

Step VI: To a stirred solution of the amide obtained in the previousstep (17.9 g, 0.077 mol) in EtOAc (35 mL) at 0° C. was added dry HCl inEtOAc (4 N, 225 mL) over a period of 30 min. After stirring at 0° C. for1 h the volatiles were removed under reduced pressure and the residuewas triturated with ether several times to obtain (2S,4S)-4-fluoropyrrolidine-2-carboxamide, hydrochloride salt as an off-white powder (12g) in 92% yield. m/z (M+1) 133; ¹H NMR (DMSO-d₆) 300 MHz δ 10.60-10.30(s (br), ½H), 8.90-8.60 (s (br), ½H), 8.10 (s (br), 1H), 7.72 (s (br),1H), 5.38 (ddd, J=3.7, 3.7, 52.4 Hz, 1H), 4.32 (d, J=10.5 Hz 1H), 4.28(d, J=10.4 Hz 1H), 3.64-3.29 (m, 2H), 2.73-2.50 (m, 1H), 2.41-2.24 (m,1H).

Step VII: To a stirred suspension of hydrochloride salt as obtained instep VI (12 g, 0.071 mol) in dichloromethane (140 mL) cooled to 0° C.was added Et₃N (30 mL, 0.213 mol), chloroacetyl chloride (8.1 mL, 0.107mol). The reaction mixture was gradually warmed to r.t. and stirred for1 h. The reaction mass was filtered through a sintered funnel, washedthe salt bed with ether and the filtrate was evaporated under vacuum toobtain a crude product(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carboxamide (14.8 g) as aviscous liquid in 3:1 mixture of rotomers. m/z (M+1) 209; ¹H NMR(DMSO-d₆) 300 MHz δ 7.26 (s (br), ½H), 7.04 (s (br), ½H), 5.34 (d,J=52.5 Hz, 0.8H), 5.25 (d, J=53.0 Hz, 0.2H), 4.58-4.30 (m, 3H),3.90-3.50 (m, 2H), 2.60-2.20 (m, 2H).

Step VIII: To a stirred solution of the compound obtained in step VII(14.7 g, 0.07 mol) in dry THF (140 mL) under N₂ atmosphere at 0° C. wasadded trifluoroacetic anhydride (15 mL, 0.107 mol). The reaction mixturewas gradually warmed to r.t. and stirred for 1 h. Water was added andthe two layers were separated. The aqueous layer was extracted withEtOAc and the combined organic layer was washed with brine, dried overanhydrous Na₂SO₄. The solvent was evaporated under reduced pressure toobtain crude product, which was purified by column chromatography toyield (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile as atan solid (8.7 g) in 64% yield (3:1 mixture of two rotomers). [α]_(D),−51.0 (c, 1.0, CHCl₃); IR cm⁻¹ 3031, 3007, 2962, 2241, 1679, 1407, 1280,12225, 1076, 860; m/z (M+1), 191; ¹H NMR (CDCl₃) 300 MHz δ 5.45 (ddd,J=3.4, 3.4, 51.3 Hz, 0.8H), 5.37 (ddd, J=3.4, 3.4, 51.0 Hz, 0.2H), 5.06(d, J=8.9 Hz, 0.2H), 4.95 (d, 9.3 Hz, 0.8H), 4.30-3.55 (m, 2H), 4.06 (s,2H), 2.65-2.55 (m, 1H), 2.50-2.25 (m, 1H).

Preparation 6(2S,4R)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile

The compound(2S,4R)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile issynthesized from (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid usingthe same sequence of steps and procedures as outlined above for(2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile startingfrom (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid.(2S,4R)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile: Solid,4:1 mixture of two rotomers; m/z (M+1) 191; ¹H NMR (CDCl₃) 300 MHz δ5.38 (d (br), J=51.3 Hz, 0.8H), 5.33 (d (t), J=51.0 Hz, 0.2H), 5.02 (d,J=8.5 Hz, 0.2H), 4.72 (d, 8.5 Hz, 0.8H), 4.40-3.30 (m, 2H), 4.06 (s,2H), 3.0-2.65 (m, 1H), 2.62-2.40 (m, 1H).

Preparation 7 (4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carbonitrile

Step I: To a stirred solution of 40% aq. formaldehyde (40 mL) at 0° C.was added in portions solid L-cystein (12.1 g, 0.1 mol) over a period of30 minutes. The reaction mixture was stirred for 4 h, after which thereaction mixture was filtered through a sintered funnel. The solids werewashed with absolute ethanol then with diethyl ether. The solids weredried under high vacuum to obtain (4R)-1,3-thiazolidine-4-carboxylicacid (12.5 g) in 94% yield. M.R, 215-217° C.; m/z (M+1) 134; IR cm⁻¹3429, 3049, 2357, 1629, 1463, 1383, 1343, 1014, 862; ¹H NMR (D₂O) 300MHz δ 4.40-4.30 (m, 2H), 4.30-4.22 (m, 1H), 3.40-3.18 (m, 2H).

Step II: To a stirred mixture of the compound obtained in step I (13.3g, 0.1 mol) in acetonitrile (400 mL) cooled to 0° C., was added pyridine(20.1 mL, 0.22 mol) and Boc-anhydride (58 mL, 0.24 mol). After stirringthe reaction mixture for 1 h at room temperature, solid NH₄HCO₃ (11.8 g,0.15 mol) was added and the reaction mixture was stirred for another 2h. The reaction mixture was partitioned between ethylacetate and 1:1mixture of 2N HCl and brine solution. The aqueous layer was extractedwith ethylacetate, the combined organic layers were dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to obtaintert-butyl (4R)-4-(aminocarbonyl)-1,3-thiazolidine-3-carboxylate (23 g)as a gummy liquid quantitatively. The product was used in the nextreaction without further purification. m/z (M+1) 233; IR cm⁻¹ 3334,2978, 2932, 1682, 1392, 1163, 763; ¹H NMR (CDCl₃) 300 MHz δ 5.70-5.50 (s(br), 1H), 4.80-4.60 (m, 2H), 4.48-4.30 (m, 1H), 3.50-3.10 (m, 2H).

Step III: To a stirred solution of tert-butyl(4R)-4-(aminocarbonyl)-1,3-thiazolidine-3-carboxylate (23 g, 0.1 mol) inethylacetate (50 mL) at 0° C. was added dry HCl in ethylacetate (3.5 N,250 mL). The resulting mixture was stirred at room temperature for 2 h,the volatiles were removed under reduced pressure and the residue wastriturated with ethylacetate several times to obtain(4R)-1,3-thiazolidine-4-carboxamide hydrochloride salt as an off-whitepowder (16.5 g) quantitatively. M.R, 201.8-203.9° C.; m/z (M+1), 133; IRcm⁻¹ 3387, 3250, 3189, 2857, 1706, 1675, 1612, 1371, 1123, 894; ¹H NMR(DMSO-d₆) 300 MHz δ 10.30-9.60 (s (br), ½H), 8.10 (s (br), ½H), 7.77 (s(br), 1H), 4.40 (t, J=7.0 Hz, 1H), 4.31 (d, J=9.6 Hz, 1H), 4.25 (d,J=9.6 Hz, 1H), 3.50-3.30 (m, 1H), 3.15 (dd, J=7.0, 11.7 Hz, 1H).

Step IV: To a stirred suspension of the hydrochloride salt obtained instep III (16.5 g, 0.1 mol) in dichloromethane (200 mL) cooled to 0° C.were added Et₃N (41 mL, 0.3 mol) and chloroacetyl chloride (8.8 mL, 0.11mol). The reaction mixture was slowly warmed to room temperature andstirred for 1 h. The reaction mass was filtered through a sinteredfunnel, the salt bed was washed with ether, and the filtrate wasevaporated under vacuum to obtain the crude product(4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carboxamide (20.8 g) as viscousliquid, which was used in the next step without further purification.m/z (M+1) 209; IR cm⁻¹ 3418, 2925, 1736, 1667, 1416, 1219, 771; ¹H NMR(CDCl₃) 300 MHz δ 6.60-6.30 (s (br), ½H), 6.0-5.65 (s (br), ½H), 5.02(dd, J=3.6, 6.9 Hz, 0.8H), 4.88-4.75 (m, 0.4H), 4.70 (d, J=8.8 Hz,0.8H), 4.62 (d, J=8.8 Hz, 0.8H), 4.51 (d, J=10.0 Hz, 0.2H), 4.16 (s,1.6H), 4.11 (s, 0.4H), 3.56 (dd, J=3.4, 11.8 Hz, 0.8H), 3.44 (dd, J=4.7,8.0 Hz, 0.4H), 3.15 (dd, J=7.1, 11.8 Hz, 0.8H), 1.28 (s, 1.6H), 1.25 (s,7.4H).

Step V: To a stirred solution of the compound obtained in step IV (20.7g, 0.1 mol) in dry THF (200 mL) under N₂ atmosphere at 0° C. was addedtrifluoroacetic anhydride (21 mL, 0.15 mol). The reaction mixture wasgradually warmed to room temperature and stirred for 1 h. The reactionmixture was diluted with water and the two layers were separated. Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed with brine and dried over anhydrous Na₂SO₄. The solvent wasevaporated under reduced pressure and the residue was purified by columnchromatography to yield(4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carbonitrile (10.0 g) asoff-white solid in 53% yield. [α]_(D), −147.24 (c, 0.5, CHCl₃); M.R,85.9-87.3° C.; m/z (M+1) 191; IR cm⁻¹ 2982, 2936, 2245, 1679, 1666,1393, 1284, 1261, 984, 788; ¹H NMR (CDCl₃) 300 MHz δ 5.29 (t, J=4.3 Hz),4.72 (d, J=8.8 Hz, 1H), 4.66 (d, J=8.8 Hz, 1H), 3.45-3.30 (m, 2H).

Preparation 8tert-Butyl(3-aminotricyclo[3.3.1.0.^(3,7)]non-1-yl)carbamate

Step I: To a solution of the carboxylic acid obtained in preparation 2step I (2.7 g, 12.9 mmol) in toluene (52 mL) at ice bath temperatureEt₃N (5.8 mL, 38.7 mmol) and diphenylphosphoryl azide (3.3 mL, 15.5mmol) were added. The reaction mixture was gradually warmed to roomtemperature, stirred for one hour, and refluxed for 4 h. Upon cooling toroom temperature, the reaction mixture was transferred to a separatoryfunnel and washed once with water. The organic layer was transferred toan RB flask cooled to ice bath temperature and aq. KOH solution (50%w/v, 26 mL) and nBu₄NI (476 mg, 1.29 mmol) were added. The mixture wasstirred at room temperature for 2 h. Upon completion of the reaction,the reaction mixture was cooled to ice bath temperature, acidified to pH2 with conc. HCl, extracted once with ether, the aqueous layer wasbasified with aq. NaOH solution (50% w/v), and extracted withchloroform. The combined organic layers were dried over anhydrous Na₂SO₄and the solvent was evaporated under reduced pressure to obtain theamino compound 1-(1-aminotricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone as aviscous liquid (1.3 g) in 56% yield. m/z (M+1) 180; ¹H NMR (CDCl₃) 300MHz δ 2.68-2.61 (m, 1H), 2.49-2.43 (m, 1H), 2.17 (s, 3H), 2.05 (ddd,J=2.3, 2.3, 10.6 Hz, 1H), 1.95-1.78 (m, 3H), 1.78-1.43 (m, 6H).

Step II: To a stirred solution of the amino compound obtained in step I(1.3 g, 7.26 mmol) in dichloromethane (29 mL) at ice bath temperatureEt₃N (2 mL, 14.5 mmol), Boc anhydride (2.1 mL, 8.7 mmol), and DMAP (44mg, 0.36 mmol) were added. After stirring for 1 h at r.t, the solventwas removed under reduce pressure and the crude reaction mass waspurified by column chromatography to obtain tert-butyl (3-acetyltricyclo[3.3.1.0^(3,7)]non-1-yl)carbamate (1.8 g) as a viscous liquid in90% yield. m/z (M+1) 280; ¹H NMR (CDCl₃) 300 MHz δ 4.73 (s (br), 1H),2.72-2.64 (m, 1H), 2.17 (s, 3H), 2.10-1.78 (m, 8H), 1.78-1.1.68 (m, 2H),1.43 (s, 9H).

Step III: To a mixture of NaOH (1.32 g, 33.0 mmol), H₂O (8.8 mL), and1,4 dioxane (2 mL) at ice bath temperature was added Br₂ (0.6 mL, 12.3mmol) and stirred for 5 minutes. The resulting hypobromite solution wasadded dropwise to a stirred solution of the compound obtained in step II(0.6 g, 2.2 mmol) in 1,4-dioxane (2.4 mL) at around 10° C. The reactionmixture was gradually warmed to r.t, stirred for 1 h, then cooled to 0°C. and quenched by adding acetic acid (2 mL, 36.3 mmol). The mixture wasdiluted with water and extracted in EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄ and the solvent was removedunder reduced pressure to obtain1-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylicacid (0.54 g) as a viscous liquid in 87% yield. m/z (M−1) 280; ¹H NMR(CDCl₃) 300 MHz δ 4.75 (s (br), 1H), 2.78-2.60 (m, 1H), 2.47-2.40 (m,1H), 2.33-2.22 (m, 1H), 2.18-1.72 (m, 8H), 1.62-1.53 (m, 1H), 1.43 (s,9H).

Step IV: To a solution of the acid (0.55 g, 1.95 mmol) obtained in stepIII in toluene (8 mL) at ice bath temperature Et₃N (1.2 mL, 8.8 mmol)and diphenylphosphoryl azide (0.5 mL, 2.3 mmol) were added. The reactionmixture was gradually warmed to r.t., stirred for one hour, and thenrefluxed for 4 h. Upon cooling to room temperature, the reaction mixturewas transferred to a separatory funnel and washed once with water. Theorganic layer was transferred to a RB flask cooled to ice bathtemperature and an aq. KOH solution (50% w/v, 4 mL) and nBu₄NI (10 mg,0.02 mmol) were added. The reaction mixture was stirred at roomtemperature for 2 h. Upon completion of the reaction, the reactionmixture was cooled to ice bath temperature, acidified to pH 2 with conc.HCl, extracted once with ether, and the aqueous layer was basified withaq. NaOH solution (50% w/v) and extracted with chloroform. The combinedorganic layers were dried over anhydrous Na₂SO₄ and the solvent wasevaporated under reduced pressure to obtain the title compoundtert-butyl(3-aminotricyclo[3.3.1.0.^(3,7)]non-1-yl)carbamate as aviscous liquid (0.3 g) in 60% yield. m/z (M+1) 253; ¹H NMR (CDCl₃) 300MHz δ 2.35-2.28 (m, 1H), 2.20-1.80 (m, 5H), 1.78-1.53 (m, 5H), 1.52-1.47(m, 1H), 1.43 (s, 9H).

Preparation 9 1-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)pyrrolidin-2-one

Step I: To a stirred solution of the compound obtained by preparation 8step I (0.9 g, 5.0 mmol) in THF (20 mL) at 0° C., Et₃N (2.1 mL, 15 mmol)and 4-chloro butyroyl chloride (1.02 g, 7.5 mmol) were added. Afterstirring the reaction mixture at room temperature for 1 h, an aqueoussolution of NaOH (50%, 10 mL) was added drop-wise followed by additionof n-Bu₄NI (182 mg, 10 mol %). After stirring the reaction mixture for16 h, it was diluted with water and extracted in EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography to obtain1-(3-acetyltricyclo[3.3.1.0^(3,7)]non-1-yl)pyrrolidin-2-one as viscousliquid (1.0 g) in 81% yield. m/z (M+1) 248; ¹H NMR. (CDCl₃) 300 MHz δ3.42 (t, J=6.5 Hz, 2H), 2.72-2.66 (m, 1H), 2.51-2.40 (m, 2H), 2.32 (t,J=7.8 Hz, 2H), 2.28-2.12 (m, 2H), 2.18 (s, 3H), 2.10-1.87 (m, 5H),1.81-1.69 (m, 2H), 1.67-1.60 (m, 2H).

Step II: To a stirred mixture of NaOH (2.4 g, 60.6 mmol), H₂O (16 mL)and 1,4 dioxane (4 mL) at ice bath temperature was added Br₂ (1.13 mL,22.6 mmol) and stirred for 5 minutes. The resulting hypobromite solutionwas added dropwise to a stirred solution of the compound obtained instep I (1.0 g, 4.04 mmol) in 1,4-dioxane (18 mL) at 10° C. Thetemperature of the reaction was brought to room temperature and thereaction mixture was stirred for 1 h. Then it was cooled to ice bathtemperature and quenched by adding acetic acid (3.9 mL, 65.7 mmol). Thereaction mixture was diluted with water, extracted with EtOAc, and thecombined organic layers were washed with brine and dried over Na₂SO₄.The solvent was removed under reduced pressure to obtain1-(2-oxopyrrolidin-1-yl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acidas a viscous liquid (1.3 g) in 100% yield. m/z (M+1) 250; ¹H NMR (CDCl₃)300 MHz δ 3.42 (t, J=7.0 Hz, 2H), 2.78-2.71 (m, 1H), 2.47-2.23 (m, 6H),2.08-1.90 (m, 6H), 1.85-1.72 (m, 2H), 1.62 (dd, J=2.4, 11.0 Hz, 1H).

Step III: To a stirred solution of the acid obtained in step II (0.5 g,2.0 mmol) in CHCl₃ (21 mL) at room temperature was added conc. H₂SO₄(1.0 mL, 20 mmol) followed by NaN₃ (0.39 g, 6.0 mmol) in portions over aperiod of 30 min., so that the temperature of the reaction did not riseabove 40° C. The reaction was warmed to 45° C. and stirred for 2 h, thencooled to ice bath temperature, diluted with water and extracted withEtOAc. The aqueous layer was basified by adding 50% NaOH solution andextracted with CHCl₃. The combined organic layer was washed with brine,dried over Na₂SO₄ and the solvent was removed under reduced pressure toobtain 1-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl) pyrrolidin-2-one as anoff-white solid (0.25 g) in 74% yield. m/z (M+1) 221; ¹H NMR (CDCl₃) 300MHz δ 3.41 (t, J=7.0 Hz, 2H), 2.46 (dd, J=2.4, 10.3 Hz, 1H), 2.38-2.28(m, 1H), 2.30 (t, J=8.3 Hz, 2H), 2.16-1.82 (m, 9H), 1.78 (dd J=2.6, 10.8Hz, 1H), 1.66-1.58 (m, 1H), 1.51 (dd, J=2.5, 10.8 Hz, 1H).

Preparation 101-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine

Step I: To a stirred solution of the compound obtained from thepreparation 8 step I (1.0 g, 5.6 mmol) in THF (23 mL) at 0° C. was addedEt₃N (1.2 mL, 8.4 mmol), followed by the addition of4-chlorobutyrylchloride (1.02 g, 7.5 mmol). After stirring the reactionmixture at r.t for 1 h, an aqueous NaOH solution (50% w/v, 11 mL) wasadded; followed by the addition of n-Bu₄NI (182 mg, 0.56 mmol). Thereaction mixture was stirred for 16 h, diluted with water, and extractedwith EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain 1-[1-(1,1-dioxido isothiazolidin-2-yl)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone as aviscous liquid (1.0 g) in 61% yield. m/z (M+1) 284; ¹H NMR (CDCl₃) 300MHz δ 3.37 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.76-2.69 (m, 1H),2.53-2.47 (m, 1H), 2.39-2.26 (m, 3H), 2.18 (s, 3H), 2.22-2.07 (m, 4H),2.20 (dd, J=3.2, 11.0 Hz, 1H), 1.96-1.89 (m, 1H), 1.78-1.69 (m, 2H),1.61 (dd, J=2.7, 11.0 Hz, 1H).

Step II: To a stirred mixture of NaOH (2.1 g, 53.0 mmol), H₂O (14 mL),and 1,4 dioxane (4 mL) at ice bath temperature was added Br₂ (1.0 mL,19.8 mmol) and the mixture was stirred for 5 minutes. Thus formedhypobromite solution was added drop-wise to a stirred solution of thecompound obtained in step I (1.0 g, 3.53 mmol) in 1,4-dioxane (7 mL) at10° C. The temperature of the reaction was gradually brought to roomtemperature and the reaction was stirred for 1 h, then it was cooled toice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol).The reaction mixture was diluted with water and extracted with EtOAc.The combined organic layer was washed with brine, dried over Na₂SO₄, andthe solvent was removed under reduced pressure to obtain 1-(1,1-dioxidoiso thiazolidin-2-yl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid asa viscous liquid (0.9 g) in 90% yield. m/z (M+1) 286; ¹H NMR (CDCl₃) 300MHz δ 3.37 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.8 Hz, 2H), 2.84-2.76 (m, 1H),2.52-2.41 (m, 2H), 2.38-2.26 (m, 2H), 2.25-1.98 (m, 6H), 1.85-1.72 (m,2H), 1.61 (dd, J=2.2, 11.3 Hz, 1H).

Step III: To a stirred solution of the acid obtained in step II (0.29 g,1.0 mmol) in CHCl₃ (5 mL) at room temperature was added conc. H₂SO₄(0.53 mL, 10 mmol) followed by the addition NaN₃ (0.2 g, 3.0 mmol) inportions over a period of 30 min; while maintaining the temperaturebelow 40° C. The reaction mixture was warmed to 45° C. and stirred for 2h. The reaction mixture was cooled to ice bath temperature, diluted withwater and extracted with EtOAc. The aqueous layer was basified by addinga 50% NaOH solution and extracted with CHCl₃. The combined organic layerwas washed with brine, dried over Na₂SO₄ and the solvent was removedunder reduced pressure to obtain1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.0^(3,7)]nonan-3-amineas a viscous liquid (0.17 g) in 66% yield. m/z (M+1) 257; ¹H NMR (CDCl₃)300 MHz δ 3.36 (t, J=6.6 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.40-2.24 (m,4H), 2.18 (dd, J=3.0, 10.4 Hz, 1H), 2.13-1.83 (m, 6H), 1.76 (dd, (J=2.4,10.8 Hz, 1H), 1.65-1.58 (m, 1H), 1.48 (dd, J=2.4, 10.8 Hz, 1H).

Preparation 11 tert-butyl(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate

Step I: To a suspension of NaH (60% dispersed in nujol, 1.92 g, 80 mmol)in THF (80 mL) cooled to ice bath temperature was added4-hydroxyadamantanone (6.64 g, 40 mmol) dissolved in THF (80 mL) via asyringe over a period of 15 minutes. After stirring the reaction mixturefor 30 min., nBu₄NI (1.4 g, 4 mmol) was added followed by the additionof benzylbromide (5.26 mL). The reaction mixture was warmed to roomtemperature and stirred for 16 h until TLC revealed disappearance ofhydroxyadamantanone. Excess NaH was quenched by adding sat. aq NH₄Clsolution to the ice cooled reaction mixture. The two layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andthe solvent was evaporated under reduced pressure to obtain a crudereaction mass which was purified by column chromatography to obtain5-(benzyloxy)adamantan-2-one as a gummy liquid (7.93 g) in 77% yield.m/z (M+1), 257; ¹H NMR (CDCl₃) 300 MHz δ 7.60-7.20 (m, 5H), 4.51 (s,2H), 2.72-2.63 (m, 2H), 2.40-2.36 (m, 1H), 2.35-1.92 (m, 10H).

Step II: Freshly prepared methylmagnesium iodide in ether (0.5M, 114mL), was added through a canula to the compound obtained in step I (7.3g, 28.5 mmol) in THF (57 mL) at 0° C. After stirring it for 0.5 h, thereaction mixture was quenched by adding sat. aq. NH₄Cl solution. Theorganic layer was separated and the aqueous layer was extracted withisopropyl ether. The combined organic layer was washed with water andbrine, dried over anhydrous Na₂SO₄, and the solvent was removed underreduced pressure to obtain 5-(benzyloxy)-2-methyl adamantan-2-ol as agummy liquid (4:6 mixture of α and β isomers) (7.5 g) in 95% yield. m/z(M+1), 273; ¹H NMR (CDCl₃) 300 MHz δ 7.42-7.20 (m, 5H), 4.51 (s, 0.8H),4.48 (s, 1.2H), 2.40-1.30 (m, 13H), 1.40 (s, 1.2H), 1.35 (s, 1.8H).

Step III: The compound obtained in step II (7.5 g, 27.5 mmol) wasdissolved in a mixture of AcOH ((5.5 mL) and THF (28 mL) and addeddrop-wise through an additional funnel to the ice cold solution of NaOCl(4%, 275 mL) over a period of 15 minutes. n-Bu₄NI (210 mg, 2 mol %) wasadded and the reaction mixture was stirred for 1.5 h. The reactionmixture was poured into a separation funnel and two layers wereseparated. The aqueous layer was extracted in diisopropylether and thecombined organic layer was washed with water and brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure. The crudeproduct was refluxed with methanolic KOH solution (3.0 g KOH in 55 mLMeOH) for 1 h. The solvent was evaporated under reduced pressure and theproduct was purified by column chromatography to obtain methylketone1-[1-(benzyloxy)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone as a gummyliquid (4.84 g) in 65% yield. m/z (M+1), 271; 1H NMR (CDCl₃) 300 MHz δ7.40-7.20 (m, 5H), 4.52 (s, 2H), 2.70-2.64 (m, 1H), 2.58-2.52 (m, 1H),2.33-2.27 (m, 1H), 2.18 (s, 3H), 2.11-1.88 (m, 5H), 1.78-1.58 (m, 4H).

Step IV: To a mixture of NaOH (10.8 g, 270 mmol), H₂O (72 mL) and1,4-dioxane (20 mL) at ice bath temperature was added Br₂ (5.2 mL, 100.8mmol) and stirred for 5 minutes. This hypobromite solution was addeddrop-wise to a solution of the compound obtained from step III (4.84 g,18 mmol) in 1,4-dioxane (18 mL) kept at ice bath temperature. Thereaction mixture was gradually warmed to room temperature and stirredfor 1 h, after which it was cooled to ice bath temperature and quenchedby adding AcOH (3.9 mL, 65.7 mmol), diluted with water, and extracted inEtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure to obtain1-(benzyloxy)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid as a gummyliquid (4.1 g) in 83% yield. m/z (M+1), 273; ¹H NMR (CDCl₃) 300 MHz δ7.40-7.20 (m, 5H), 4.52 (s, 2H), 2.78-2.70 (m, 1H), 2.58-2.48 (m, 1H),2.45-2.37 (m, 1H), 2.18-1.50 (m, 9H).

Step V: To a solution of the acid obtained from step IV (1.36 g, 5 mmol)in toluene (20 mL) at ice bath temperature was added Et₃N (2.1 mL, 15mmol) and diphenylphosphoryl azide (DPPA, 1.3 mL, 6 mmol). The reactionmixture was slowly warmed to room temperature and stirred for one hour,after which the temperature was risen to reflux for 4 h. Upon cooling toroom temperature, it was transferred to a separatory funnel and washedonce with water. The organic layer was transferred back to the RB flaskcooled to ice bath temperature and aq. KOH solution (50% w/v, 10 mL) andnBu₄NI (92 mg, 0.25 mmol) were added. The reaction mixture was stirredat room temperature for 2 h. Upon completion of the reaction, thereaction mixture was cooled to ice bath temperature, acidified to pH 2with conc, HCl, extracted once with ether, and the aqueous layer wasbasified with aq. NaOH solution (50% w/v), and extracted withchloroform. The combined organic layer was dried over anhydrous Na₂SO₄and the solvent was evaporated under reduced pressure to obtain pureamine 1-(benzyloxy)tricyclo[3.3.1.0^(3,7)]nonan-3-amine as a gummyliquid (614 mg) in 80% yield. m/z (M+1), 244; 1H NMR (CDCl₃) 300 MHz δ2.40-2.20 (m, 5H), 2.70-2.48 (m 3H), 2.40 (s (br), 1H), 2.27-2.16 (m,1H), 2.10-1.40 (m, 9H).

Step VI: To a solution of the amino compound obtained from step V (590mg, 2.4 mmol) in dichloromethane (10 mL) at ice bath temperature wasadded Et₃N (0.5 mL, 3.6 mmol) followed by addition of Boc anhydride (654mg, 3.0 mmol). The reaction mixture was stirred at room temperature for1 h. The solvent was removed under reduce pressure and the crudereaction mass was purified by column chromatography using EtOAc/hexanesas eluent to obtain the Boc derivative of tert-butyl(1-benzyloxytricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate as a gummy liquid(740 mg) in 90% yield. m/z (M+1), 343; ¹H NMR (CDCl₃) 300 MHz δ7.40-7.20 (m, 5H), 4.80-4.70 (s (br), 1H), 4.51 (s, 2H), 2.50-2.25 (m,4H), 2.0-1.75 (m, 6H), 1.65-1.50 (m, 2H), 1.46 (s, 9H).

Step VII: A mixture of the compound obtained from step VI (730 g, 2.1mmol) and Pd(OH)₂/C (20% wet, 150 mg) in MeOH (9 mL) was stirred underH₂ atmosphere at room temperature for 2 h. The reaction mixture wasfiltered through a pad of celite and the filtrate was concentrated underreduced pressure to obtain tert-butyl (1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate as an off-white solid (520 mg)in 97% yield. m/z (M+1), 254; ¹H NMR (CDCl₃) 300 MHz δ 4.72 (s (br),1H), 2.48-2.35 (m, 2H), 2.32-2.18 (m, 2H), 1.93-1.70 (m, 6H), 1.55-1.35(m, 2H), 1.45 (s, 9H).

Example 1

Step I: A stirred mixture of[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methylmethanesulfonate (2.4 g, 7.5 mmol) [as obtained from preparation 2],K₂CO₃ (4.5 g, 34.2 mmol), and 1,2,4-triazole (1.5 g, 22.5 mmol) in DMF(30 mL) was heated to 110° C. for 5 h. The reaction mixture was cooledto room temperature, diluted with water, and extracted withethylacetate. The combined organic layer was washed with brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methyl}-1H-1,2,4-triazole(1.82 g) as a viscous liquid in 85% yield. m/z (M+1) 290; IR cm⁻¹ 2932,1668, 1506, 1441, 1373, 1311, 1211, 1140, 1047, 876, 753. ¹H NMR (CDCl₃)300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 4.03-3.92 (m, 4H),2.42-2.32 (m, 2H), 1.86-1.79 (m, 1H), 1.74-1.65 (m, 2H), 1.52-1.37 (m,8H), 1.26 (s, 3H).

Step II: A stirred solution of1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methyl}-1H-1,2,4-triazole(2.6 g, 9.09 mmol) obtained from Step I and p-toluenesulfonic acid (0.16g) in acetone (36 mL) was refluxed for 4 h. The volatiles were removedunder reduced pressure and the residue was diluted with ethylacetate,washed with 10% aq. NaHCO₃ and brine, dried over Na₂SO₄, and the solventwas evaporated under reduced pressure to obtain1-[1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone(2.2 g, 86% yield) as a viscous liquid. m/z (M+1) 246; ¹H NMR (CDCl₃)300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.10 (s, 2H), 2.75-2.65 (m, 1H),2.49-2.42 (m, 1H), 2.16 (s, 3H), 2.0-1.45 (m, 10H). ¹³C NMR (CDCl₃) 75MHz δ 211.0, 151.6, 143.6, 61.6, 56.9, 48.2, 45.9, 45.7, 42.6, 41.9,37.3, 36.6, 26.3.

Step III: To a stirred solution of NaOH (1.75 g, 43.8 mmol), H₂O (14.6mL) and 1,4 dioxane (2 mL) at ice bath temperature was added Br₂ (0.8mL, 16.4 mmol) and the mixture was stirred for 5 minutes. The resultinghypobromite solution was added drop-wise to a stirred solution of1-[1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]ethanone(0.7 g, 2.92 mmol) in 1,4-dioxane (4 mL) at ice bath temperature. Thereaction mixture was gradually warmed to room temperature and stirredfor 1 h. Then it was cooled to ice bath temperature and quenched byadding AcOH (3.9 mL, 65.7 mmol). The crude reaction mixture was dilutedwith water and extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄, and the solvent was removed underreduced pressure to obtain1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylicacid (0.54 g) in 75% yield as an off-white solid. M.R: 230-235° C. m/z(M+1) 248. IR cm⁻¹ 3436, 3102, 2924, 2511, 1937, 1689, 1523, 1308, 1137,979, 732. ¹H NMR (CD₃OD) 300 MHz δ 8.43 (s, 1H), 7.9 (s, 1H), 4.17 (s,2H), 2.70-2.62 (m, 1H), 2.40-2.33 (m, 1H), 2.06-1.95 (m, 2H),1.84-1.1.43 (m, 8H).

Step IV: To a stirred suspension of1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylicacid (0.13 g, 0.52 mmol) obtained in step III, in CHCl₃ (2.6 mL) wasadded conc. H₂SO₄ (0.25 mL, 5.2 mmol). To this homogenous solution NaN₃(0.1 g, 1.56 mmol) was added in portions over a period of 30 minutes,while keeping the temperature of the reaction below 40° C. Afterstirring the reaction mixture for 2 h at r.t., the reaction mixture wascooled to ice bath temperature, diluted with water and extracted withEtOAc. The aqueous layer was basified by adding 50% aq. NaOH solutionand extraction with CHCl₃. The combined organic layer was washed withbrine, dried over Na₂SO₄ and the solvent was removed under reducedpressure to obtain1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine(0.08 g) as a viscous liquid in 70% yield. m/z (M+1) 219; ¹H NMR (CDCl₃)300 MHz δ 7.98 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 2.38-2.30 (m, 1H),2.06-1.98 (m, 1H), 1.96-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.55-1.36 (m,4H).

Step V: To a stirred mixture of1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine(0.06 g, 0.38 mmol) and K₂CO₃ (0.13 g, 0.96 mmol) in DMSO (1 mL) at anice bath temperature was added compound(2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.07 g, 0.32 mmol). Thereaction mixture was gradually warmed to room temperature and stirredfor 3 h. Upon completion of the reaction (checked by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain thetriazole derivative of(2S)-1-[1H-1,2,4-triazol-1-ylmethyl(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile (0.07 g) in 60% yield as an off-whitesolid, M.R: 230-235° C. m/z (M+1) 355. IR cm⁻¹ 3429, 2929, 2224, 1658,1511, 1426, 1330, 1276, 1141, 1018, 747. ¹H NMR (CDCl₃) 300 MHz δ 8.0(s, 1H), 7.9 (s, 1H), 4.78 (bd, J=6.3 Hz, 1H), 4.09 (s, 2H), 3.65-3.35(m, 4H), 2.40-2.05 (m, 8H), 1.80-1.62 (m, 4H), 1.58-1.32 (m, 4H).

Example 2

To a stirred mixture of the triazole amine as obtained in step IV inexample 1 (0.65 g, 3 mmol) and K₂CO₃ (1.24 g, 9 mmol) in DMSO (12 mL) atice bath temperature was added(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.57 g, 3mmol). The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S,4S)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white powder (0.4 g) in 36% yield. IR cm⁻¹ 3444, 2951, 1672,1518, 1416, 1301, 1135, 935; m/z (M+1) 373; ¹H NMR (CDCl₃) 300 MHz δ 8.0(s, 1H), 7.92 (s, 1H), 5.44 (ddd, J=3.4, 3.4, 51.2 Hz, 0.8H), 5.35 (ddd,J=3.4, 3.4, 51.3 Hz, 0.2H), 5.04 (t, J=8.8 Hz, 0.2H), 4.95 (d, 9.2 Hz,0.8H), 4.10 (s, 2H), 4.05-3.51 (m, 2.4H), 3.4 (s (br), 1.6H), 2.82-2.62(m, 1H), 2.45-2.16 (m, 5H), 1.91-1.69 (m, 4H), 1.57-1.38 (m, 4H).

Example 3

To a stirred mixture of the triazole amine as obtained in step IV inexample 1 (0.4 g, 1.83 mmol) and K₂CO₃ (0.4 g, 2.8 mmol) in DMSO (4 mL)at ice bath temperature was added(2S,4R)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.35 g,1.83 mmol). The reaction mixture was gradually warmed to roomtemperature and stirred for 3 h. Upon completion of the reaction(checked by TLC), the reaction mixture was diluted with EtOAc and washedwith water and brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography to obtain(2S,4R)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas a gummy liquid (0.21 g) as a mixture of two rotamers in 25% yield.m/z (M+1), 373; ¹H NMR (CDCl₃) 300 MHz δ 8.0 (s, 1H), 7.92 (s, 1H), 5.35(d (br), J=51.5 Hz, 0.8H), 5.30 (d (br), J=51.3 Hz, 0.2H), 4.97 (t,J=8.4 Hz, 0.2H), 4.80 (t, 8.4 Hz, 0.8H), 4.20-3.32 (m, 4H), 4.10 (s,2H), 2.87-2.40 (m, 1H), 2.40-2.33 (m, 1H), 2.25-2.15 (m, 1H), 1.98-1.38(m, 11H).

Example 4

To a stirred mixture of the triazole amine as obtained in step IVexample 1 (0.27 g, 1.05 mmol) and K₂CO₃ (0.58 g, 4.2 mmol) in DMSO (4mL) at ice bath temperature was added(4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carbonitrile (0.2 g, 1.05mmol). The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(4R)-3-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrileas a light yellow solid (0.18 g) in 46% yield. m/z (M+1) 373; ¹H NMR(CDCl₃) 300 MHz δ 7.99 (s, 1H), 7.92 (s, 1H), 5.32 (t, J=4.1 Hz, 1H),4.70-4.55 (m, 2H), 4.08 (s, 2H), 3.62-3.48 (m, 2H), 3.40-3.26 (m, 2H),2.42-2.35 (m, 1H), 2.25-2.15 (m, 1H), 1.90-1.39 (m, 10H).

Example 5

Step I: A mixture of {3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl methanesulfonatesas obtained in preparation 3 (0.8 g, 2.3 mmol), K₂CO₃ (0.95 g, 6.9mmol), tetrazole (0.24 g, 3.45 mmol), and DMF (10.0 mL) was heated to110° C. for 12 h. The reaction mixture was cooled to room temperature,diluted with water, and extracted with EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography to obtain tert-butyl[1-(1H-tetrazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate asa viscous liquid (0.2 g) in 27% yield. m/z (M+1) 320; ¹H NMR (CDCl₃) 300MHz δ 8.48 (s, 1H), 4.72 (s (br), 1H), 4.56 (s, 2H), 2.52-2.43 (m, 1H),2.37-2.30 (m, 1H), 2.20-1.80 (m, 4H), 1.72 (ddd, J=2.7, 12.3, 15.4 Hz,2H), 1.56-1.38 (m, 4H), 1.44 (s, 9H).

Step II: To a stirred solution of the compound obtained in step I above(0.2 g, 0.62 mmol) in EtOAc (2.0 mL) cooled to ice bath temperature wasadded a solution of dry HCl in EtOAc (3N, 3 mL). The reaction mixturewas stirred at the same temperature for 2 h and the volatiles wereremoved under reduced pressure to obtain the crude product, which wastriturated with ether several times to obtain pure hydrochloride salt of1-(1H-tetrazol-1-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine (160 mg)in 100% yield. m/z (M+1) 220; 1H NMR (CD₃OD) 300 MHz δ 8.72 (s, 1H),4.70 (s, 2H), 2.52-2.43 (m, 1H), 2.42-2.37 (m, 1H), 2.0-1.80 (m, 5H),1.70-1.50 (m, 5H).

Step III: To a stirred solution of the hydrochloride salt obtained instep II (0.162 g, 0.62 mmol) in DMSO (2.5 mL) at room temperature undernitrogen atmosphere was added(2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.11 g, 0.62 mmol) andK₂CO₃ (0.34 g, 2.48 mmol). After stirring the reaction mixture for 3 h,it was diluted with EtOAc, and washed with water and brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain(2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.09 g) in 40% yield. m/z (M+1) 355; 1H NMR(CDCl₃) 300 MHz δ 8.49 (s, 1H), 4.77 (d, J=6.7 Hz, 1H), 4.56 (s, 2H),3.64-3.38 (m, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 6H), 1.80-1.65 (m, 5H),1.60-1.40 (m, 5H).

Example 5A

Hydrochloride salt: To a stirred solution of the compound obtained inexample 5 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. was addedTMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removedunder reduced pressure and the residue was triturated several times withether to obtain off-white hydrochloride salt of(2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile(38 mg).

Example 6

Step I: A mixture of {3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl methanesulfonatesas obtained in preparation 3 (0.85 g, 2.4 mmol), K₂CO₃ (1.0 g, 7.2mmol), N-methylpiperazine (0.37 mL, 3.6 mmol) and DMF (10.0 mL) washeated to 110° C. for 12 h. The reaction mixture was cooled to roomtemperature, diluted with water and extracted in EtOAc. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and the solventwas removed under reduced pressure. The crude product was purified bycolumn chromatography to obtain tert-butyl[1-(4-methylpiperazin-1-yl)methyl]tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamateas a viscous liquid (0.39 g) in 46% yield. m/z (M+1) 350; ¹H NMR (CDCl₃)300 MHz δ 4.72 (s (br), 1H), 2.55-2.25 (m, 10H), 2.48 (s, 3H), 2.38 (s,2H), 2.0-1.85 (m, 4H), 1.80-1.72 (m, 1H), 1.70-1.40 (m, 4H), 1.45 (s,9H), 1.35-1.22 (m, 1H).

Step II: To a stirred solution of the compound obtained according tostep I (0.38 g, 1.09 mmol), in EtOAc (4.0 mL) cooled to ice bathtemperature was added a solution of dry HCl in EtOAc (3 N, 6 mL). Thereaction mixture was stirred at the same temperature for 2 h and thevolatiles were removed under reduced pressure to obtain a crudeproducts, which was triturated with diethyl ether several times toobtain1-[(4-methylpiperazin-1-yl)methyl]tricyclo[3.3.1.0^(3,7)]nonan-3-aminehydrochloride salt (330 mg) in 85% yield.

Step III: To a stirred solution of the hydrochloride (0.33 g, 0.92 mmol)obtained in Step II, in DMSO (3.7 mL) at room temperature under nitrogenatmosphere (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.92mmol) and K₂CO₃ (0.76 g, 5.53 mmol) were added. After stirring thereaction mixture for 3 h, it was diluted with EtOAc and washed withwater and brine, dried over Na₂SO₄, and the solvent was removed underreduced pressure. The crude product was purified by columnchromatography to obtain (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.12 g)in 47% yield. m/z (M+1) 386; ¹H NMR (CDCl₃+CD₃OD) 300 MHz δ 4.78 (d,J=5.7 Hz, 1H), 3.85-3.50 (m, 4H), 3.30-3.10 (m, 5H), 2.85-2.70 (m, 8H),2.52-2.45 (m, 2H), 2.38-2.20 (m, 4H), 2.10-1.90 (m, 4H), 1.70-1.40 (m,5H), 1.40-1.27 (m, 1H).

Example 6A

Hydrochloride Salt: To a stirred solution of the compound obtained inexample 7 (39 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. was addedTMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles were removedunder reduced pressure and the residue was triturated several times withdiethyl ether to obtain(2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrilehydrochloride salt as an off-white solid (41 mg).

Example 7

Step I: A mixture of {3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl methanesulfonatesas obtained in preparation 3 (0.85 g, 2.4 mmol), K₂CO₃ (1.0 g, 7.2mmol), thiomorpholine (0.4 mL, 3.6 mmol) and DMF (10.0 mL) was heated to110° C. for 12 h. The reaction mixture was cooled to room temperature,diluted with water and extracted with EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography to obtain tert-butyl[1-(thiomorpholin-4-ylmethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamateas a viscous liquid (0.18 g) in 21% yield. m/z (M+1) 353; ¹H NMR (CDCl₃)300 MHz δ 4.72 (s (br), 2.75-2.66 (m, 4H), 2.65-2.58 (m, 4H), 2.40-2.28(m, 2H), 2.17 (s, (2H), 2.0-1.85 (m, 4H), 1.80-1.72 (m, 1H), 1.62-1.50(m, 4H), 1.45 (s, 9H), 1.35-1.20 (m, 1H).

Step II: To a stirred solution of the compound (0.22 g, 0.63 mmol)obtained in step I, in EtOAc (2.0 mL) cooled to ice bath temperature wasadded a solution of dry HCl in EtOAc (3 N, 4 mL). The reaction mixturewas stirred at same temperature for 2 h and the solvent was removedunder reduced pressure to obtain a crude product, which was trituratedseveral times with diethyl ether to obtain 1-(thiomorpholin-4-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine hydrochloride salt (180 mg) in 88%yield.

Step III: To a stirred solution of the hydrochloride salt (0.17 g, 0.51mmol) obtained in step II above in DMSO (2.0 mL) at room temperatureunder nitrogen atmosphere was added(2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.52 mmol) andK₂CO₃ (0.35 g, 2.55 mmol. After stirring the reaction mixture for 3 h,it was diluted with EtOAc and washed with water and brine, dried overNa₂SO₄ and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain(2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.07 g) in 35% yield. m/z (M+1) 389; ¹H NMR(CDCl₃) 300 MHz δ 4.83-4.75 (m, 1H), 3.90-3.45 (m, 4H), 2.85-2.70 (m,4H), 2.70-2.60 (m, 4H), 2.48-2.35 (m, 2H), 2.35-2.15 (m, 4H), 2.0-1.75(m, 4H), 1.68-1.40 (m, 5H), 1.38-1.25 (m, 1H).

Example 7A

Hydrochloride salt: To a stirred solution of the compound obtained inexample 7 (39 mg, 0.1 mmol), in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain the hydrochloride salt of(2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas off-white solid (41 mg).

Example 8

Step I: A stirred mixture of[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methylmethanesulfonate as obtained in preparation 2 (1.0 g, 2.9 mmol), K₂CO₃(1.16 g, 8.7 mmol) and isothiazolidine-1,1-dioxide (0.53 g, 4.35 mmol)in DMF (12.0 mL) was heated to 110° C. for 16 h. The reaction mixturewas cooled to room temperature, diluted with water and extracted withEtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄ and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain2-{[3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.0^(3,7)]non-1-yl]methyl}isothiazolidine1,1-dioxide as a viscous liquid (0.69 g) in 70% yield. m/z (M+1) 342; ¹HNMR (CDCl₃) 300 MHz δ 4.04-3.92 (m, 4H), 3.30 (t, J=6.8 Hz, 2H), 3.10(t, J=7.4 Hz, 2H), 2.94 (d, J=14.6 Hz, 1H), 2.87 (d, J=14.6 Hz, 1H),2.40-2.27 (m, 4H), 1.88-1.72 (m, 2H), 1.72-1.55 (m, 4H), 1.55-1.38 (m,4H), 1.27 (s, 3H).

Step II: A stirred solution of the compound obtained by Step I (0.68 g,2.0 mmol) and p-toluenesulfonic acid (38 mg, 0.2 mmol) in acetone (8 mL)was refluxed for 4 h. The reaction mixture was diluted with EtOAc andwashed with 10% aq. NaHCO₃ and brine, dried over Na₂SO₄, and the solventwas evaporated under reduced pressure to obtain 1-{1-[(1,1-dioxidoisothiazolidin-2-yl)methyl]tricyclo[3.3.1.0^(3,7)]non-3-yl}ethanone(0.55 g) in 92% yield as a viscous liquid.

Step III: To a stirred mixture of NaOH (1.2 g, 27.8 mmol), H₂O (8 mL),and 1,4 dioxane (1 mL) at ice bath temperature was added Br₂ (0.56 mL,10.4 mmol) and the mixture was stirred for 15 minutes. The resultinghypobromite solution was added drop-wise to a stirred solution of thecompound obtained in step II (0.55 g, 1.85 mmol) in 1,4-dioxane (3 mL)at ice bath temperature. The reaction mixture was gradually warmed toroom temperature and after stirring for 1 h; it was cooled to ice bathtemperature and quenched by adding AcOH (1.7 mL, 27.8 mmol). Thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄, and thesolvent was removed under reduced pressure to obtain1-[(1,1-dioxidoisothiazolidin-2-yl)methyl]tricyclo[3.3.1.0^(3,7)]nonane-3-carboxylicacid(0.39 g) in 70% yield. m/z (M−1) 298; ¹H NMR (CDCl₃) 300 MHz δ 3.32 (t,J=6.8 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.95 (s, 2H), 2.80-2.73 (m, 1H),2.43-2.41 (m, 1H), 2.40-2.29 (m, 2H), 2.10-2.0 (m, 2H), 1.82-1.72 (m,3H), 1.67-1.54 (m, 4H), 1.46 (dd, J=3.2, 11.0 Hz, 1H).

Step IV: To a stirred solution of the acid obtained in step III (0.39 g,1.31 mmol) in CHCl₃ (7 mL) was added conc. H₂SO₄ (1.4 mL, 26 mmol).Solid NaN₃ (0.26 g, 3.93 mmol) was added slowly in portions by keepingthe reaction temperature below 40° C. The reaction mixture was stirredat r.t for 2, h then it was cooled to ice bath temperature, diluted withwater, and extracted with EtOAc. The aqueous layer was basified byadding 50% NaOH solution and extracted with CHCl₃. The combined organiclayer was washed with brine, dried over Na₂SO₄, and the solvent wasevaporated under reduced pressure to obtain1-[(1,1-dioxidoisothiazolidin-2-yl)methyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amine (0.26 g) as viscous liquidin 74% yield. m/z (M+1) 271; ¹H NMR (CDCl₃) 300 MHz δ 3.32 (t, J=6.8 Hz,2H), 3.10 (t, J=7.4 Hz, 2H), 2.92 (s, 2H), 2.40-2.28 (m, 3H), 2.01-1.83(m, 3H), 1.75-1.52 (m, 6H), 1.50-1.43 (m, 1H), 1.39-1.32 (m, 1H).

Step V: To a stirred mixture of the amine obtained in step IV (0.26 g,0.96 mmol) and K₂CO₃ (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bathtemperature was added under nitrogen atmosphere(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol).After stirring the reaction mixture for 3 h at r.t, it was diluted withEtOAc, washed with water and brine, dried over Na₂SO₄, and the solventwas evaporated under reduced pressure. The crude product was purified bycolumn chromatography to obtain(2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.17 g) in 43% yield. m/z (M+1) 407; ¹H NMR(CDCl₃) 300 MHz δ 4.87-4.76 (m, 1H), 3.70-3.40 (m, 2H), 3.44 (s, 2H),3.32 (t, J=6.7 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.93 (s, 2H), 2.41-2.10(m, 8H), 1.90-1.46 (m, 7H), 1.43-1.35 (m, 1H).

Example 9

Step I: A mixture of the compound obtained in preparation 3 (0.9 g, 2.6mmol), K₂CO₃ (1.1 g, 7.8 mmol) and thiazolidine-2,4-dione (0.47 g, 4.0mmol) in DMF (10.5 mL) was heated to 110° C. for 12 h. The reactionmixture was cooled to room temperature, diluted with water, andextracted with EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain3{3-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.0^(3,7)]non-1-yl}methyl-1,3-thiazolidine-2,4-dioneas a viscous liquid (0.28 g) in 25% yield. m/z (M+1) 367; ¹H NMR (CDCl₃)300 MHz δ 4.72 (s (br), 1H), 3.96 (s, 2H), 3.57 (s, 2H), 2.46-2.38 (m,1H), 2.38-2.30 (m, 1H), 2.02-1.85 (m, 4H), 1.80-1.70 (m, 1H), 1.63 (dd,J=2.9, 10.5 Hz, 1H), 1.52-1.40 (m, 3H), 1.44 (s, 9H), 1.37 (dd, J=3.0,11.0 Hz, 1H).

Step II: To a stirred solution of the compound obtained in step I (0.2g, 0.54 mmol) in EtOAc (2.0 mL) cooled to ice bath temperature was addeda solution of dry HCl in EtOAc (3N, 3 mL). The reaction mixture wasstirred at the same temperature for 2 h and the solvent was removedunder reduced pressure to obtain a crude product, which was trituratedwith diethyl ether several times to obtain the hydrochloride salt (165mg) in 100% yield. m/z (M+1) 267; ¹H NMR (CD₃OD) 300 MHz δ 4.10 (s, 2H),3.60 (dd, J=9.0, 11.0 Hz, 2-H), 2.48-2.42 (m, 1H), 2.34 (ddd, J=1.6,6.9, 8.5 Hz, 1H), 1.88-1.68 (m, 6H), 1.68-1.53 (m, 3H), 1.50 (dd, J=2.0,11.4 Hz, 1H).

Step III: To a stirred solution of the hydrochloride salt obtained instep II (0.165 g, 0.54 mmol) in DMSO (2.2 mL) at room temperature undernitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile(0.1 g, 0.54 mmol) and K₂CO₃ (0.23 g, 1.62 mmol) was added sequentially.After stirring the reaction mixture for 3 h, it was diluted with EtOAcand washed with water and brine, dried over Na₂SO₄, and the solvent wasremoved under reduced pressure. The crude product was purified by columnchromatography to obtain(2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.11 g) in 50% yield. m/z (M+1) 358; 1H NMR(CDCl₃) 300 MHz δ 4.77 (d, J=7.4 Hz, 1H), 3.96 (s, 2H), 3.75-3.38 (m,2H), 3.56 (s, 2H), 3.41 (s, 2-H), 2.40-2.10 (m, 6H), 1.90-1.57 (m, 10H),1.57-1.33 (m, 4H).

Example 10

Step I: To a stirred solution of tert-butyl[1-(hydroxymethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate (as obtainedin step VI preparation 3) (0.67 g, 2.5 mmol) in toluene (10 mL) wasadded phthalimide (0.52 g, 3.5 mmol), triphenylphosphine (1.05 g, 4.0mmol), and diisopropylazodicarboxylate (0.8 mL, 4.0 mmol). The reactionmixture was heated to 90° C. for 4 h. The volatiles were removed underreduced pressure and the residue was purified by column chromatographyto obtain tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate(0.45 g) as a viscous liquid in 46% yield. m/z (M+1) 397; ¹H NMR (CDCl₃)300 MHz δ 7.90-7.80 (m, 2H), 7.77-7.68 (m, 2H), 4.75 (s (br), 1H), 3.60(s, 2H), 2.47-2.35 (m, 1H), 2.36-2.29 (m, 1H), 2.02-1.84 (m, 4H),1.77-1.65 (m, 2H), 1.64-1.35 (m, 5H), 1.41 (s, 9H), 1.34-1.24 (m, 1H).

Step II: To a stirred solution of the compound obtained from step I(0.45 g, 1.12 mmol) in dichloromethane (1.1 mL) at 0° C. was addedtrifluoroacetic acid (1.1 mL). The reaction mixture was gradually warmedto room temperature and stirred for 1 h. The volatiles were removedunder vacuum and the residue was triturated several times with diethylether to obtain2-[(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)methyl]-1H-isoindole-1,3(2H)-dione(0.4 g) as its trifluoroacetic acid salt in 86% yield. m/z (M+1) 297; ¹HNMR (DMSO-d₆) 300 MHz δ 8.05 (s (br), 2H), 7.92-7.80 (m, 4H), 3.51 (s,2H), 2.38-2.30 (m, 1H), 2.30-2.22 (m, 1H), 1.85-1.66 (m, 6H), 1.60-1.50(m, 3H), 1.45-1.38 (m, 1H).

Step III: To a stirred mixture of the compound obtained from step II(0.4 g, 0.98 mmol) and K₂CO₃ (0.54 g, 3.92 mmol) in DMSO (4.0 mL) at icebath temperature under nitrogen atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol).After stirring the reaction mixture at r.t for 3 h, it was diluted withEtOAc and washed with water and brine, dried over Na₂SO₄, and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography to obtain(2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.18 g) in 43% yield. m/z (M+1) 433; ¹H NMR(CDCl₃) 300 MHz δ 7.90-7.80 (m, 2H), 7.75-7.65 (m, 2-H), 4.86-4.72 (m,1H), 3.72-3.38 (m, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 7H),1.90-1.78 (m, 2H), 1.70-1.40 (m, 3H).

Example 11

Step I: To a stirred solution ofbenzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate(1.1 g, 3.03 mmol) obtained from preparation 4, in THF (30 mL) at 0° C.was added Et₃N (0.66 mL, 4.6 mmol) and 3-chloropropanesulfonylchloride(0.42 mL, 3.3 mmol). The reaction mixture was warmed to room temperatureand stirred for 1 h. An aqueous solution of NaOH (50% w/v, 6 mL) wasadded followed by addition of n-Bu₄NI (56 mg, 0.15 mmol). After stirringthe reaction mixture for 16 h, it was diluted with water and extractedin EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography to obtainbenzyl[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamateas an off-white solid (0.93 g) in 66% yield. M.R: 215.6-219.2° C. m/z(M+1) 467; IR cm⁻¹ 3441, 2953, 1716, 1516, 1314, 1215, 770. ¹H NMR(CDCl₃) 300 MHz δ 7.40-7.16 (m, 9H), 5.13-5.0 (bs, 2H), 3.75 (t, J=6.6Hz, 2H), 3.35 (t, J=7.5 Hz, 2H), 2.59-2.38 (m, 4H), 2.30-1.60 (m, 10H).

Step II: A mixture ofbenzyl[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate(0.8 g, 1.7 mmol) obtained in step I, Pd/C (10%, 0.4 g) in MeOH (17 mL)was stirred at room temperature under H₂ atmosphere for 2 h. Thereaction mixture was filtered through a pad of celite and the filtratewas concentrated under reduced pressure to obtain1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amineas an off-white solid (0.49 g) in 85% yield. m/z (M+1) 333; IR cm⁻¹3418, 1652, 1137, 772. ¹H NMR (CDCl₃) 300 MHz, δ 7.31 (d, J=8.8 Hz, 2H),7.22 (d, J=8.8 Hz, 2H), 3.78 (t, J=6.6 Hz, 2H), 3.43 (t, J=7.4 Hz, 2H),2.58-2.47 (m, 3H), 2.40-2.34 (m, 1H), 2.27-2.11 (m, 2H), 2.10-1.95 (m,4H), 1.93-1.70 (m, 4H).

Step III: To a stirred mixture of1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amine(0.4 g, 1.2 mmol) and K₂CO₃ (0.48 g, 3.6 mmol) in DMSO (4.8 mL) at icebath temperature was added(2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.25 g, 1.44 mmol). Thereaction mixture was gradually warmed to room temperature and stirredfor 3 h. Upon completion of the reaction (checked by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas a white solid (0.28 g) in 50% yield. M.R, 214-216° C. m/z (M+1) 469;IR cm⁻¹ 3436, 2932, 2240, 1658, 1517, 1414, 1308, 1137, 952, 740. ¹H NMR(300 MHz, CD₃OD) δ: 7.35 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.85(t, J=5.4 Hz, 1H), 4.15-3.95 (m, 2H), 3.81-3.70 (m, 3H), 3.60-3.50 (m,1H), 3.42 (t, J=7.4 Hz, 2H), 2.65-2.45 (m, 4H), 2.40-1.75 (m, 14H).

Example 12

To a stirred mixture of1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amine(as obtained in example 8 Step II) (0.17 g, 0.5 mmol) and K₂CO₃ (0.21 g,1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5mmol). The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrileas an off-white powder (0.09 g) in 37% yield as a 3:1 mixture of tworotomers. IR cm⁻¹ 3438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078,955; m/z (M+1) 487; ¹H NMR (CDCl₃) 300 MHz δ 7.25 (d, J=6.2 Hz, 2H),7.20 (d, J=8.6 Hz, 2H), 5.42 (d (br), J=51.0 Hz, 0.8H), 5.34 (d (br),J=50.4 Hz, 0.2H), 5.15 (d, J=10.2 Hz, 0.2H), 4.98 (d, J=7.4 Hz, 0.8H),4.0-3.50 (m, 4H), 3.76 (t, J=6.5H, 2H), 3.35 (t, J=6.5 Hz, 2H),2.80-2.28 (m, 6H), 2.15-1.58 (m, 10H).

Example 13

To a stirred mixture of1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amineas obtained in example 8 step II (0.22 g, 0.7 mmol) and K₂CO₃ (0.3 g,2.1 mmol) in DMSO (3.4 mL) at ice bath temperature was added(2S,4R)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.13 g, 2.1mmol). The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(2S,4R)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrileas an off-white powder (0.14 g) as a 3:1 mixture of two rotomers in 43%yield. m/z (M+1) 487; ¹H NMR (CDCl₃) 300 MHz δ 7.25 (d, J=7.9 Hz, 2H),7.20 (d, J=8.7 Hz, 2H), 5.35 (d (br), J=51.4 Hz, 0.8H), 5.28 (d (br),J=50.7 Hz, 0.2H), 5.02 (t, J=7.2 Hz, 0.2H), 4.80 (t, J=8.4 Hz, 0.8H),4.02-3.41 (m, 4H), 3.76 (t, J=6.6H, 2H), 3.37 (t, J=7.4 Hz, 2H),2.85-2.25 (m, 6H), 2.15-1.55 (m, 10H).

Example 14

To a stirred mixture of1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.0^(3,7)]nonan-3-amineas obtained in example 8 step II (0.25 g, 1.1 mmol) and K₂CO₃ (0.46 g,3.3 mmol) in DMSO (5 mL) at ice bath temperature was added(4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carbonitrile (0.2 g, 1.1 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(4R)-3-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrileas an off-white powder (0.1 g) in 40% yield. m/z (M+1) 487; IR cm⁻¹3444, 2952, 2873, 1672, 1518, 1416, 1301, 1135, 953; ¹H NMR (CDCl₃) 300MHz δ 7.25 (d, J=6.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 5.38-5.48 (m, 1H),4.72-4.51 (m, 2H), 3.75 (t, J=6.6 Hz, 2H), 3.70-3.55 (m, 1H), 3.36 (t,J=7.4 Hz, 2H), 3.32-3.20 (m, 1H), 2.60-2.40 (m, 4H), 2.20-1.58 (m, 10).

Example 15

Step I: To a stirred solution ofbenzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate(1.1 g, 3.03 mmol) obtained in preparation 4, in THF (30 mL) at 0° C.was added sequentially Et₃N (0.66 mL, 4.6 mmol) and4-chlorobutyrylchloride (0.37 mL, 3.3 mmol). The reaction mixture waswarmed to room temperature and stirred for 1 h. An aqueous solution ofNaOH (50% w/v, 6 mL) was added followed by addition of n-Bu₄NI (56 mg,0.15 mmol) and the reaction was stirred for 16 h. The reaction mixturewas diluted with water and extracted in EtOAc. The combined organiclayer was washed with brine, dried over Na₂SO₄, the solvent was removedunder reduced pressure, and the crude product was purified by columnchromatography to obtainbenzyl[2-[4-(2-Oxopyrrolidin-1-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamateas an off-white solid (0.9 g, 69% yield). m/z (M+1) 431; ¹H NMR (CDCl₃)300 MHz δ 7.55 (d, J=8.6 Hz, 2H), 7.42-7.20 (m, 7H), 5.15-5.0 (bs, 2H),3.87 (t, J=7.0 Hz, 2H), 2.67-2.53 (m, 3H), 2.48-2.42 (m, 1H), 2.35-1.55(m, 12H).

Step II: A mixture ofbenzyl[2-[4-(2-Oxopyrrolidin-1-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate(0.73 g, 1.7 mmol) obtained in step I and Pd/C (10%, 0.4 g) in MeOH (17mL) was stirred at room temperature under H₂ atmosphere for 2 h. Thereaction mixture was filtered through a pad of celite and the filtratewas concentrated under reduced pressure to obtain1-[4-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)phenyl]pyrrolidin-2-one asan off-white solid (0.43 g, 85% yield). m/z (M+1) 297; ¹H NMR (CDCl₃)300 MHz δ 7.52 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H), 3.86 (t, J=6.9Hz, 2H), 2.62 (t, J=7.9 Hz, 2H), 2.52-2.42 (m, 1H), 2.32-1.60 (m, 13H).

Step III: To a stirred solution of1-[4-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)phenyl]pyrrolidin-2-oneobtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 mL) at an ice bathtemperature under nitrogen atmosphere was added K₂CO₃ (0.48 g, 3.6 mmol)followed by addition of (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile(0.21 g, 1.2 mmol). After stirring the reaction mixture at r.t for 3 h,it was diluted with EtOAc and washed with water and brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain the titlecompound(2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas a white solid (0.26 g) in 50% yield. M.R: 254-256° C.; m/z (M+1) 433;¹H NMR (300 MHz, CDCl₃) δ: 7.54 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz,2H), 4.30-4.20 (m, 1H), 4.06-4.18 (m, 2H), 3.87 (t, J=7.0 Hz, 1H),3.80-3.50 (m, 4H), 2.64 (t, J=7.8 Hz, 2H), 2.58-1.60 (m, 18H).

Example 16

To a stirred mixture of the lactam amine,1-[4-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)phenyl]pyrrolidin-2-one asobtained in example 12, Step II, (0.15 g, 0.5 mmol) and K₂CO₃ (0.21 g,1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5mmol). The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S,4S)-4-fluoro-1-{N-[2-[4-(2-oxopyrrolidin-1-1)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas off-white powder (0.11 g) in 49% yield. m/z (M+1) 451; ¹H NMR (CDCl₃)300 MHz δ 7.51 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 5.43 (ddd,J=3.1, 3.1, 51.3 Hz, 1H), 5.12 (d, J=8.7 Hz, 0.2H), 4.97 (d, J=9.5H),4.05-3.62 (m, 2H), 3.85 (t, J=6.9 Hz, 2H), 3.55-3.40 (m, 2H), 2.81-2.61(m, 1H), 2.60 (t, J=8.2 Hz, 2H), 2.49-2.40 (m, 1H), 2.32-2.25 (m, 1H),2.21-2.05 (m, 4H), 2.0-1.60 (m, 9H).

Example 17

To a stirred mixture of the lactam amine obtained in example 12, step II(0.15 g, 0.5 mmol) and K₂CO₃ (0.21 g, 1.5 mmol) in DMSO (2 mL) at icebath temperature was added(4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carbonitrile (0.1 g, 1.1 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄ and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(4R)-3-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-1,3-thiazolidine-4-carbonitrileas an off-white powder (0.09 g) in 40% yield. m/z (M+1), 451; ¹H NMR(CDCl₃) 300 MHz δ 7.51 (d, J=6.7 Hz, 2H), 7.24 (d, J=7.0 Hz, 2H), 5.34(t, J=4.1 Hz, 1H), 4.65 (d, J=7.5 Hz, 1H), 4.60 (d, J=7.5 Hz, 1H), 3.85(t, J=6.9 Hz, 2H), 3.70-3.55 (m, 2H), 3.40-3.25 (m, 2H), 2.60 (t, J=7.8Hz, 2H), 2.49-2.42 (m, 1H), 2.33-2.25 (m, 1H), 2.21-2.02 (m, 4H),2.0-1.6 (m, 8H).

Example 18

Step I: To a stirred solution ofbenzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamateobtained from preparation 4 (1.09 g, 3.0 mmol) in glacial acetic acid(12 mL) was added 2,5-dimethoxytetrahydrofuran (0.44 g, 3.3 mmol). Thereaction mixture was heated under reflux for 1 h. The mixture wasdiluted with ethylacetate, washed with water, 10% aq. NaHCO₃ and brine.The combined organic layer was dried over anhydrous Na₂SO₄ and thesolvent was evaporated under reduced pressure. The crude product waspurified by column chromatography to obtainbenzyl[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate(0.8 g) in 65% yield as a viscous liquid. m/z (M+1) 413; ¹H NMR (CDCl₃)300 MHz δ 7.50-7.20 (m, 9H), 7.08-7.04 (m, 2H), 6.37-6.30 (m, 2H), 5.10(s, 2H), 2.65-2.52 (m, 1H), 2.50-2.42 (m, 1H), 2.40-2.12 (m, 2H),2.10-1.70 (m, 6H), 1.70-1.52 (m, 2H).

Step II: To a stirred solution of the compound obtained from step I (0.8g, 1.94 mmol) in MeOH (20 mL) Pd/C (10%, 0.1 g) was added. The reactionmixture was stirred at r.t. for 2 h under H₂ pressure with a balloon.The reaction mixture was filtered through a pad of celite and thefiltrate was concentrated under reduced pressure to obtain2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-amine(0.45 g) as a viscous liquid (0.45 g) in 83% yield. m/z (M+1) 279; ¹HNMR (CD₃OD) 300 MHz δ 7.40-7.25 (m, 4H), 7.20-7.05 (m, 2H), 6.30-6.20(m, 2H), 2.57-2.46 (m, 1H), 2.46-2.38 (m, 1H), 2.30-2.13 (m, 2H),2.13-1.81 (m, 7H), 1.80-1.70 (m, 1H).

Step III: To a stirred mixture of the compound obtained from step II(0.41 g, 1.5 mmol) and K₂CO₃ (0.62 g, 4.5 mmol) in DMSO (6 mL) at icebath temperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in32% yield as off-white solid. m/z (M+1) 415; ¹H NMR (CDCl₃) 300 MHz δ7.38-7.26 (m, 4H), 7.10-7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m,1H), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50-2.42 (m, 1H), 2.38-2.28 (m,2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H).

Example 19

Step I: To a stirred solution of benzyl[2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate obtained bypreparation 4 (1.09 g, 3.0 mmol) in THF (12 mL) at 0° C. was added Et₃N(0.65 mL, 4.5 mmol), followed by addition of 2-chloro ethylisocyanate(0.3 mL, 3.3 mmol). The reaction mixture was warmed to room temperatureand stirred for 1 h. An aqueous solution of NaOH (50% w/v, 6 mL) wasadded followed by n-Bu₄NI (55 mg, 0.15 mmol) and the reaction mixturewas stirred for 16 h. The two layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic layer was washedwith brine, dried over Na₂SO₄ and the solvent was evaporated underreduced pressure. The crude product was purified by columnchromatography to obtainbenzyl[2-[4-(2-oxoimidazolidin-1-yl]hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate(0.7 g) as an off-white solid in 54% yield. m/z (M+1) 432; ¹H NMR(CDCl₃) 300 MHz δ 7.44 (d, J=8.8 Hz, 2H), 7.40-7.30 (m, 5H), 7.21 (d,J=8.8 Hz, 2H), 5.09 (s, 2H), 3.92 (t, J=7.4 Hz, 2H), 3.55 (t, J=8.5 Hz,2H), 2.59-2.50 (m, 1H), 2.44-2.38 (m, 1H), 2.30-2.11 (m, 3H), 2.11-1.90(m, 3H), 1.89-1.66 (m, 2H), 1.64-1.46 (m, 2H).

Step II: To a stirred solution of the compound obtained from step I(0.65 g, 1.5 mmol) in MeOH (15 mL) Pd/C (10%, 0.1 g) was added. Thereaction mixture was stirred at room temperature for 2 h under H₂pressure with a balloon. The reaction mixture was filtered through a padof celite and the filtrate was concentrated under reduced pressure toobtain 1-[4-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)phenyl]imidazolidin-2-one (0.4 g) as anoff-white solid in 90% yield. M.R: 215-220° C.; m/z (M+1) 298; IR cm⁻¹3412, 3245, 2955, 1687, 1518, 1485, 1263, 805; ¹H NMR (CDCl₃+DMSO-d₆)300 MHz δ 8.26 (s (br), 2H), 7.46 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz,2H), 6.70 (s (br), 1H), 3.86 (t, J=7.3 Hz, 2H), 3.48 (t, J=7.3 Hz, 2H),2.50-2.45 (m, 1H), 2.22-2.07 (m, 3H), 2.02-1.63 (m, 8H).

Step III: To a stirred mixture of the compound obtained from step II(0.4 g, 1.35 mmol) and K₂CO₃ (0.56 g, 4.05 mmol) in DMSO (6 mL) at icebath temperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was evaporated under reducedpressure. The crude product was purified by column chromatography toobtain(2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; ¹H NMR(CDCl₃) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H),4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40(m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70(m, 12H), 1.65-1.57 (m, 1H).

Example 20

Step I: To a stirred mixture of tricyclo[3.3.1.0^(3,7)]nonan-3-amine(0.28 g, 2.0 mmol) and K₂CO₃ (0.83 g, 6.0 mmol) in DMSO (8 mL) at icebath temperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S)-1-[(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrileas a viscous liquid (0.23 g) in 42% yield. m/z (M+1) 274; 1H NMR (CDCl₃)300 MHz δ 4.87-4.76 (m, 1H), 3.71-3.40 (m, 2H), 3.41 (s, 2H), 2.35-2.05(m, 7H), 1.92-1.74 (m, 6H), 1.68-1.48 (m, 4H).

Example 19A

Hydrochloride salt: To a stirred solution of the compound obtained inexample 18 (27 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain hydrochloride salt of(2S)-1-[(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrileas an off-white solid (31 mg). m/z (M+1) 274; ¹H NMR (DMSO-d₆) 300 MHz δ9.44 (s (br), 2H), 4.86 (dd, J=4.4, 7.0 Hz, 1H), 4.10-3.88 (m, 2H),3.78-3.65 (m, 1H), 3.60-3.47 (m, 1H), 2.48-2.41 (m, 1H), 2.34-2.27 (m,2H), 2.26-2.17 (m, 2H), 2.10-1.99 (m, 2H), 1.99-1.83 (m, 6H), 1.63-1.43(m, 4H).

Example 21

Step I: To a stirred solution of tert-butyl(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate as obtained inpreparation 11 (500 mg, 1.97 mmol) in EtOAc (5 mL) cooled to ice bathtemperature was added a solution of dry HCl in EtOAc (4N, 5 mL). Afterthe reaction mixture was stirred for 2 h, the volatiles were removedunder reduced pressure. The crude product was triturated with diethylether several times to obtain 3-aminotricyclo[3.3.1.0^(3,7)]nonan-1-olhydrochloride (280 mg) in 75% yield. m/z (M+1) 154; 1H NMR (CD₃OD) 300MHz δ 2.51-2.44 (m, 1H), 2.34 (ddd, J=2.0, 7.0, 8.9 Hz, 1H), 2.17-2.04(m, 2-H), 1.94-1.71 (m, 6H), 1.60-1.53 (m, 2H).

Step II: To a stirred mixture of the compound obtained in step I (280mg, 1.5 mmol) and K₂CO₃ (820 mg, 6 mmol) in DMSO (6 mL) at ice bathtemperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain(2S)-1-{[(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileas a viscous liquid (150 mg) in 35% yield. m/z (M+1) 291; ¹H NMR (CDCl₃)300 MHz δ 4.78 (d, J=7.0 Hz, 1H), 3.75-3.38 (m, 2H), 3.43 (s, 2H),2.45-37 (m 1H), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H).

Example 22

Step I: To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol)in THF (40 mL) cooled to ice bath temperature was addedhydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via asyringe over a period of 15 minutes. After stirring the reaction mixturefor 30 min., iodomethane (1.38 mL, 22 mmol) was added. The reactionmixture was warmed to room temperature and stirred for 16 h until TLCrevealed completion of the reaction. Excess NaH was quenched by addingsaturated aq. NH₄Cl solution to the ice cooled reaction mixture. The twolayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to obtaincrude reaction mass which was purified by column chromatography to yield5-methoxyadamantan-2-one (3.0 g) in 83% yield. m/z (M+1), 181; ¹H NMR(CDCl₃) 300 MHz δ 3.26 (s, 3H), 2.67-2.61 (m, 2H), 2.39-2.33 (m, 1H),2.20-1.93 (m, 10H).

Step II: Freshly prepared methyl magnesium iodide in ether (1M, 32 mL),was added through a canula to 5-methoxyadamantan-2-one (3.0 g, 16 mmol)in THF (32 mL) at 0° C. After stirring the mixture at 0° C. for 0.5 h,the reaction mixture was quenched by adding saturated aq. NH₄Clsolution. The organic layer was separated and the aqueous layer wasextracted with diethyl ether. The combined organic layer was washed withwater and brine, dried over anhydrous Na₂SO₄, and the solvent wasevaporated under reduced pressure to obtain5-methoxy-2-methyladamantan-2-ol as 1:1 anomeric mixture (3.0 g yield,96%). m/z (M+23), 219; ¹H NMR (CDCl₃) 300 MHz δ 3.24 (s, 1½H), 3.23 ((s,1½H), 2.68-2.62 (m, 1H), 2.40-1.55 (m, 10H), 1.53-1.35 (m, 2H), 1.38 (s,3H).

Step III: 5-methoxy-2-methyladamantan-2-ol (3.0 g, 15 mmol), dissolvedin a mixture of AcOH (3.0 mL) and THF (15 mL) was added dropwise by adropping funnel to an ice bath cooled solution of NaOCl (4%, 150 mL)over a period of 15 minutes. n-Bu₄NI (0.55 g, 1.5 mmol) was added andthe reaction mixture was stirred for 1.5 h. The reaction mixture wasseparated into two layers. The aqueous layer was extracted withdiisopropylether and the combined organic layer was washed with waterand brine, dried over Na₂SO₄, and the solvent was evaporated underreduced pressure to obtain hypochlorite which was diluted with methanol(30 mL) and solid KOH (1.68 g, 30 mmol) was added. The reaction mixturewas refluxed for 1 h. The volatiles were removed and the crude productwas diluted with ether, washed with water, brine, dried over anhydrousNa₂SO₄, and the solvent was evaporated under vacuum. The crude productwas purified by column chromatography to obtain1-(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone (1.92 g) in 66%yield. m/z (M+1) 195; ¹H NMR (CDCl₃) 300 MHz δ 3.29 (s, 3H), 2.69-2.62(m, 1H), 2.57-2.50 (m, 1H), 2.26-2.16 (m, 1H), 2.18 (s, 3H), 2.10-1.61(m, 7H), 1.59-1.52 (m, 2H).

Step IV: To a mixture of NaOH (5.8 g, 147 mmol), H₂O (40.0 mL) and 1,4dioxane (10 mL) at ice bath temperature was added Br₂ (2.8 mL, 55.0mmol) and stirred for 5 minutes. The resulting hypobromite solution wasadded drop-wise to a stirred solution of1-(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone obtained from stepIII (1.9 g, 9.8 mmol), in 1,4-dioxane (10 mL) at ice bath temperature.The reaction mixture was gradually warmed to room temperature andstirred for 1 h. The reaction mixture was cooled to ice bath temperatureand AcOH (3.9 mL, 65.7 mmol) were added. The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layerwas washed with brine, dried over Na₂SO₄, and the solvent was removedunder reduced pressure to obtain1-methoxytricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid (1.3 g) in 72%yield. m/z (M+1), 197; 1H NMR (CDCl₃) 300 MHz δ 3.30 (s, 3H), 2.78-2.70(m, 1H), 2.57-2.48 (m, 1H), 2.38-2.28 (m, 1H), 2.11-2.0 (m, 2H),1.86-1.69 (m, 5H), 1.59-1.51 (m, 2H).

Step V: To the suspension of1-methoxytricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid obtained fromstep IV (0.39 g, 2.0 mmol) in CHCl₃ (10 mL) was added conc. H₂SO₄ (1.0mL, 20 mmol). Solid NaN₃ (0.39 g, 6.0 mmol) was added in portions bykeeping the reaction temperature below 40° C. After stirring at roomtemperature for 2 hrs, the reaction mixture was cooled to ice bathtemperature, diluted with water and extracted with EtOAc. The aqueouslayer was basified by adding 50% NaOH solution and extracted with CHCl₃.The combined organic layer was washed with brine, dried over Na₂SO₄, andthe solvent was removed under reduced pressure to obtain1-methoxytricyclo[3.3.1.0^(3,7)]nonan-3-amine (0.23 g) in 69% yield. m/z(M+1) 168; ¹H NMR (CDCl₃) 300 MHz δ 3.27 (s, 3H), 2.40-2.34 (m, 1H),2.16-2.08 (m, 1H), 1.97 (ddd, J=2.0, 6.8, 8.7 Hz, 1H), 1.92-1.53 (m,7H), 1.51-1.38 (m, 2H).

Step VI: To a stirred solution of the amino compound obtained by step V(0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol)and K₂CO₃ (0.4 g, 2.9 mmol). The reaction mixture was gradually warmedto room temperature and stirred for 3 h. The reaction mixture wasdiluted with EtOAc and washed with water ad brine, dried over Na₂SO₄,and the solvent was removed under reduced pressure. The crude productwas purified by column chromatography to obtain(2S)-1-{[(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile(0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl₃) 300 MHz δ 4.82-4.75(m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68(13H), 1.57-1.41 (m, 2H).

Example 16A

Hydrochloride salt: To a stirred solution of the compound prepared inexample 16 (30 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain(2S)-1-{[(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrilehydrochloride salt as off-white solid (30 mg).

Example 23

The process is as given for the methoxy compound prepared in Example 16,with the difference that in the first step ethylating agent n-Bu₄NI andethylbromide are used; the remaining process is similar.

Step I: To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol)in THF (40 mL) cooled to ice bath temperature was addedhydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via asyringe over a period of 15 minutes. The reaction mixture was stirredfor 30 min then n-Bu₄NI (0.74 g, 2 mmol) and ethyl bromide (1.6 mL, 22mmol) were added. The reaction mixture was warmed to room temperatureand stirred for 16 h. After cooling the reaction mixture to 0° C., theexcess NaH was quenched by adding sat. aq. NH₄Cl solution. The twolayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to obtaina crude reaction mass, which was purified by column chromatography toyield 5-ethoxyadamantan-2-one (3.0 g) in 77% yield. m/z (M+1) 195; 1HNMR (CDCl₃) 300 MHz δ 3.47 (q, J=7.0 Hz, 2H), 2.67-2.60 (m, 2H),2.38-2.30 (m, 1H), 2.13-1.78 (m, 10H), 1.17 (t, J=7.0 Hz, 3H).

Step II: 5-Ethoxy-2-methyladamantan-2-ol from 5-Ethoxyadamantan-2-one,as 1:1 anomeric mixture (1.6 g) in 99% yield. m/z (M+23) 233; ¹H NMR(CDCl₃) 300 MHz δ 3.51-3.41 (m, 2H), 2.31-2.23 (m, 1H), 2.18-2.05 (m,2H), 2.02-1.80 (m, 4H), 1.79-1.47 (m, 7H), 1.46-1.32 (m, 4H), 1.16 (t,J=6.5 Hz, 3H).

Step III: 1-(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone from5-Ethoxy-2-methyladamantan-2-ol in 66% yield. m/z (M+1) 209; ¹H NMR(CDCl₃) 300 MHz δ 3.49 (q, J=7.1 Hz, 2H), 2.69-2.61 (m, 1H), 2.56-2.48(m, 1H), 2.22-2.18 (m, 1H), 2.17 (s, 3H), 2.02-1.84 (m, 4H), 1.78-1.50(m, 5H), 1.18 (t, J=7.1 Hz, 3H).

Step IV: 1-ethoxytricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acidprepared from 1-(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone in 68%yield. m/z (M+1) 195; ¹H NMR (CDCl₃) 300 MHz δ 3.49 (q, J=6.7 Hz, 2H),2.75-2.68 (m, 1H), 2.52-2.47 (m, 1H), 2.36-2.28 (m, 1H), 2.10-1.95 (m,2H), 1.83 (s, 1.86-1.68 (m, 5H), 1.54 (ddd, J=3.0, 10.9, 13.6 Hz 2H),1.18 (t, J=6.7 Hz, 3H).

Step V: 1-Ethoxytricyclo[3.3.1.0^(3,7)]nonan-3-amine from1-ethoxytricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid in 53% yield.m/z (M+1) 182; ¹H NMR (CDCl₃) 300 MHz δ 3.49 (q, J=7.0 Hz, 2H),2.39-2.32 (m, 1H), 2.16-2.07 (m, 1H), 1.99-1.92 (m, 1H), 1.92-1.75 (m,5H), 1.71-1.38 (m, 4H), 1.17 (t, J=7.0 Hz, 3H).

Step VI: Coupling reaction between amine from step V and cyanopyrrolidine compound to form(2S)-1-{[(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrilein 41% yield. m/z (M+1) 318; ¹H NMR (CDCl₃) 300 MHz δ 4.81-4.75 (m, 1H),3.75-3.40 (m, 6H), 2.45-2.37 (m, 1H), 2.36-2.13 (m, 4H), 2.12-1.95 (m,2H), 1.88-1.68 (m, 6H), 1.56 (ddd, J=3.0, 3.0, 10.5 Hz 1H), 1.49-1.41(m, 1H), 1.17 (t, J=7.0 Hz, 3H).

Example 17A

Hydrochloride salt: To a stirred solution of the compound obtained fromexample 17 (32 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain the hydrochloride salt of(2S)-1-{[(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileas an off-white solid (30 mg). m/z (M+1) 318; ¹H NMR (DMSO-d₆) 300 MHz δ9.41 (s (br), 2H), 4.86 (dd, J=4.6, 6.8 Hz, 1H), 4.10-3.90 (m, 2H),3.75-3.65 (m, 1H), 3.57-3.25 (m, 3H), 2.48-2.38 (m, 2H), 2.30-2.17 (m,2H), 2.16-2.0 (m, 4H), 1.90-1.14 (m, 6H), 1.53-1.40 (m, 2H), 1.06 (t,J=7.0 Hz, 3H).

Example 24

Step I: To a stirred mixture of the compound obtained in preparation 8(0.3 g, 1.2 mmol) and K₂CO₃ (0.5 g, 3.6 mmol) in DMSO (5 mL) at ice bathtemperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.14 g, 0.83 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtaintert-Butyl-(2S)-1-{[(1-aminotricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate]acetyl}pyrrolidine-2-carbonitrileas a viscous liquid (0.18 g) in 40% yield. m/z (M+1) 389; ¹H NMR (CDCl₃)300 MHz δ 4.79 (d, J=7.5 Hz, 1H), 4.70 (s (br), 1H), 3.70-3.40 (m, 2H),3.46 (s, 2H), 2.40-2.32 (m, 1H), 2.32-1.90 (m, 6H), 1.90-1.63 (m, 5H),1.55-1.43 (m, 1H).

Step II: To a stirred solution of the compound obtained in step I (0.04g, 0.1 mmol) in EtOAc (2 mL) cooled to ice bath temperature was added asolution of dry HCl in EtOAc (3N, 2 mL). The reaction mixture wasstirred for 2 h and the solvent was removed under reduced pressure toobtain a crude product which was triturated with diethyl ether severaltimes to obtain dihydrochloride salt of(2S)-1-{[(1-aminotricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile(0.02 g) in 69% yield. m/z (M+1) 289; ¹H NMR (DMSO-d₆) 300 MHz δ 9.69 (s(br), 2H), 8.57 (s (br), 3H), 4.86 (dd, J=4.4, 7.0 Hz, 1H), 4.16-3.90(m, 2H), 3.78-3.65 (m, 1H), 3.65-3.50 (m, 1H), 2.60-2.55 (m, 1H),2.50-2.43 (m, 1H), 2.35-2.18 (m, 4H), 2.13-1.98 (m, 2H), 2.10-2.0 (m,3H), 1.96-1.70 (m, 5H), 1.68-1.60 (m, 1H), 1.50-1.43 (m, 2H).

Example 25

Step I: To a stirred solution of tert-butyl(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate obtained frompreparation 11 (1.1 g, 4.34 mmol) in dichloromethane cooled to −15° C.,under N₂ atmosphere was added diethylaminosulfur trifluoride (0.85 mL,6.51 mmol). The reaction mixture was stirred at this temperature for 1 hand subsequently stirred at room temperature for 16 h. The reactionmixture was cooled to ice bath temperature and quenched by adding amixture of crushed ice and solid NaHCO₃ (1.1 g, 13 mmol). Two layerswere separated and the aqueous layer was extracted with chloroform. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure. The crudeproduct was purified by column chromatography to obtain tert-butyl(1-fluorotricyclo[3.3.1.0^(3,7)]non-3-yl)carbamate (0.26 g) as viscousliquid in 24% yield. m/z (M−1) 254; ¹H NMR (CDCl₃) 300 MHz δ 2.55-2.40(m, 1H), 2.01.75 (m, 2H), 1.70-1.40 (m, 9H), 1.57 (s, 6-H), 1.45 (s,3H).

Step II: To a stirred solution of the compound obtained from step I(0.25 g, 0.98 mmol) in EtOAc (1 mL) cooled to ice bath temperature wasadded a solution of dry HCl in EtOAc (3N, 3 mL). After stirring thereaction mixture for 2 h, the volatiles were removed under reducedpressure. The crude product was triturated with ether several times toobtain 1-fluorotricyclo[3.3.1.0^(3,7)]nonan-3-amine, hydrochloride salt(0.19 g) in 99% yield. m/z (M+1) 156; ¹H NMR (DMSO-d₆) 300 MHz δ 8.45 (s(br), 2H), 2.47-2.18 (m, 4H), 1.96-1.72 (m, 6-H), 1.63 (dd, J=2.6, 9.5Hz, 1H), 1.50-1.42 (m, 1H).

Step III: To a stirred mixture of the hydrochloride salt obtained fromstep II (0.19 g, 0.98 mmol) and K₂CO₃ (0.53 g, 4.0 mmol) in DMSO (4.0mL) at ice bath temperature under nitrogen atmosphere(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) wasadded. After stirring the reaction mixture at r.t. for 3 h, the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38%yield. m/z (M+1) 292; 1H NMR (CDCl₃) 300 MHz δ 4.80-4.73 (m, 1H),3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, 1H), 2.87-2.08 (m, 6H),2.0-1.60 (m, 6H), 1.50-1.42 (m, 1H).

Example 23A

Hydrochloride salt: To a stirred solution of the compound obtained fromexample 23 (29 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with ether to obtain hydrochloride salt of(2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrileas an off-white solid (30 mg).

Example 26

Step I: To a stirred mixture of1-(3-aminotricyclo[3.3.1.0^(3,7)]non-1-yl)pyrrolidin-2-one prepared asin preparation 9 (0.25 g, 1.1 mmol) and K₂CO₃ (0.46 g, 3.3 mmol) in DMSO(5 mL) at an ice bath temperature was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.2 g, 1.1 mmol). Thereaction mixture was gradually warmed to room temperature and stirredfor 3 h. Upon completion of the reaction (checked by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas a viscous liquid (0.16 g) in 40% yield. m/z (M+1) 357; ¹H NMR (CDCl₃)300 MHz δ 4.78 (d, J=7.4 Hz, 1H), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41(t, J=7.0 Hz, 2H), 2.60 (dd, J=4.0, 10.2 Hz, 1H), 2.40-1.75 (m, 17H),1.72-1.62 (m, 1H), 1.58-1.50 (m, 1H).

Example 20A

Hydrochloride salt: To a stirred solution of the compound obtained fromexample 19 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with ether to obtain the hydrochloride salt of(2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas off-white solid (38 mg).

Example 27

Step I: To a stirred mixture of1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.0^(3,7)]nonan-3-amineprepared as in preparation 10 (0.17 g, 0.66 mmol), and K₂CO₃ (0.28 g,2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (by TLC), the reactionmixture was diluted with EtOAc and washed with water and brine, driedover Na₂SO₄, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography to obtain(2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; ¹H NMR (CDCl₃)300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H),3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99(m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H).

Example 21A

Hydrochloride salt: To a stirred solution of the compound obtained inexample 20 (39 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain the hydrochloride salt of(2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (41 mg). m/z (M+1) 393; ¹H NMR (DMSO-d₆) 300 MHz δ9.60 (s (br), 2H), 4.86 (dd, J=4.4, 7.0 Hz, 1H), 4.12-3.96 (m, 2H),3.59-3.47 (m, 2H), 3.28 (t, J=6.8 Hz, 2H), 3.19 (t, J=7.5 Hz, 2H),2.43-2.37 (m, 1H), 2.31-2.13 (m, 8H), 2.10-1.97 (m, 3H), 1.96-1.76 (m,5H), 1.50-1.43 (m, 1H).

Example 28

Step I: To a stirred mixture of NaOH (2.4 g, 60.0 mmol), H₂O (16 mL),and 1,4 dioxane (2 mL) at ice bath temperature was added Br₂ (0.56 mL,10.4 mmol) and stirred for 15 minutes. The resulting hypobromitesolution was added dropwise to a stirred solution of1-(1-phenyltricyclo[3.3.1.0^(3,7)]non-3-yl)ethanone obtained frompreparation I (1.0 g, 4.0 mmol) in 1,4-dioxane (6 mL) at ice bathtemperature. After stirring the reaction mixture at r.t. for 1 h, it wasagain cooled to ice bath temperature and quenched by adding AcOH (3.6mL, 60 mmol). The reaction mixture was diluted with water and extractedwith EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and the solvent was removed under reduced pressure to obtain1-phenyltricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid (0.62 g) in 64%yield. m/z (M+1) 243; ¹H NMR (CDCl₃) 300 MHz δ 7.40-7.25 (m, 4H),7.25-7.18 (m, 1H), 2.90-2.86 (m, 1H), 2.54-2.48 (m, 1H), 2.38 (ddd,J=2.0, 2.0, 11.0 Hz, 1H), 2.20-2.05 (m, 4H), 1.98-1.78 (m, 5H), 1.70(dd, J=2.8, 11.5 Hz, 1H).

Step II: To a stirred solution of1-phenyltricyclo[3.3.1.0^(3,7)]nonane-3-carboxylic acid (0.6 g, 2.48mmol) obtained from step I and triethylamine (1.0 mL, 7.44 mmol) intoluene (10 mL) under N₂ atmosphere at ice bath temperature was addeddiphenylphosphoryl azide (0.64 mL, 3.0 mmol). The reaction mixture waswarmed to room temperature and stirred for 1 h, then it was refluxed for4 h. The reaction mixture was cooled to r.t., washed with water andstirred with aq. KOH solution (50% w/v, 5.0 mL) and nBu₄NI (92 mg, 0.25mmol) for 2 h at r.t. The reaction mixture was cooled to ice bathtemperature, acidified with conc. HCl to pH 2, extracted with diethylether. The aqueous layer was basified with aq. NaOH solution (50% w/v)and extracted with chloroform. The combined organic layer was dried overanhydrous Na₂SO₄ and the solvent was evaporated under reduced pressureto obtain 1-phenyltricyclo[3.3.1.0^(3,7)]nonan-3-amine (0.33 g) asviscous liquid in 62% yield. m/z (M+1) 214; 1H NMR (CDCl₃) 300 MHz δ7.40-7.22 (m, 4H), 7.22-7.15 (m, 1H), 2.42-2.35 (m, 1H), 2.20-2.05 (m,2H), 2.02-1.52 (m, 9H).

Step III: To a stirred mixture of the compound obtained from step II(0.2 g, 0.94 mmol) and K₂CO₃ (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at icebath temperature under nitrogen atmosphere(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol)was added. After stirring the reaction mixture for 3 h at r.t., it wasdiluted with EtOAc and washed with water and brine, dried over Na₂SO₄,and the solvent was removed under reduced pressure. The crude productwas purified by column chromatography to obtain(2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrileas off-white solid (0.16 g) in 48% yield. m/z (M+1) 350; ¹H NMR (CDCl₃)300 MHz δ 7.35-7.16 (m, 5H), 4.4.85-4.76 (m, 1H), 3.76-3.40 (m, 2H),3.50 (s, 2H), 2.48-2.41 (m, 1H), 2.36-2.27 (m, 2H), 2.23-2.0 (m, 6H),1.94-1.68 (m, 4H), 1.66-1.60 (m, 1H).

Example 26A

Hydrochloride salt: To a stirred solution of the compound obtained fromexample 26 (35 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. wasadded TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with diethyl ether to obtain the hydrochloride salt of(2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrileas an off-white solid (38 mg).

Example 29

To a stirred mixture of1-(4-nitrophenyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine as obtained inStep III preparation 4 (0.77 g, 3.0 mmol) and K₂CO₃ (1.25 g, 9.0 mmol)in DMSO (12 mL) at ice bath temperature under N₂ atmosphere was added(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.51 g, 3.0 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction, the reaction mixturewas diluted with EtOAc and washed with water and brine, dried overNa₂SO₄ and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography to obtain(2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas an off-white solid (0.5 g) in 42% yield. m/z (M+1) 395; ¹H NMR(CDCl₃) 300 MHz δ 8.14 (d, J=8.9 Hz, 2H), 7.41 ((d, J=8.9 Hz, 2H),4.83-4.73 (m, 1H), 3.78-3.40 (m, 2H), 3.48 (s, 2H), 2.51-2.45 (m, 1H),2.37-2.06 (m, 6H), 2.02-1.60 (m, 9H).

Example 30

To a stirred solution of the compound obtained from example 29 (0.2 g,0.51 mmol) in a 1:2:4 mixture of water, THF, and ethanol (7 mL)respectively was sequentially added solid NH₄Cl (0.1 g, 1.87 mmol) andFe powder (0.1 g, 1.78 mmol). The reaction mixture was heated to refluxfor 2 h. After cooling the reaction mixture to room temperature, it wasfiltered through a small pad of celite and washed the bed with EtOAc.The filtrate was evaporated under reduced pressure and the residue wasdiluted with water and extracted with EtOAc. The combined organic layerwas washed with water, dried over anhydrous Na₂SO₄, and the solvent wasevaporated under reduced pressure to obtain(2S)-1-{N-[2-(4-aminophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileas off-white solid (0.09 g) in 50% yield. m/z (M+1) 365; ¹H NMR (CDCl₃)300 MHz δ 7.05 (d, J=8.5 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 4.90-4.75 (m,1H), 3.80-3.40 (m, 4H), 2.45-1.70 (m, 15H), 1.65-1.57 (m, 1H).

Example 31

Step I: A stirred mixture of the compound obtained in preparation 3 (1.1g, 3.18 mmol), sodium cyanide (0.164 g, 3.5 mmol) in DMF (7.0 mL) washeated to 110° C. for 12 h. The reaction mixture was cooled to roomtemperature, diluted with water, and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andthe solvent was removed under reduced pressure. The crude product waspurified by column chromatography to obtain tert-butyl[1-(cyanomethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate as viscousliquid (0.3 g) in 34% yield. m/z (M+1), 277; ¹H NMR (CDCl₃) 300 MHz δ4.73 (bs, 1H), 2.60-2.35 (m, 2H), 2.31 (s, 2H), 2.20-1.40 (s, 10H), 1.45(s, 9H).

Step II: To a stirred solution of the compound obtained from step I(0.25 g, 0.9 mmol) in a 1:1-mixture of ethanol and water (9 mL) at roomtemperature was added hydroxylamine hydrochloride (0.32 g, 4.5 mmol)followed by solid Na₂CO₃ (0.57 g, 5.4 mmol). The reaction mixture wasrefluxed for 12 h. The volatiles were removed under reduced pressure andthe residue was dissolved in ethylacetate and washed with water. Theorganic layer was dried over anhydrous Na₂SO₄ and evaporated underreduced pressure. The residue was dissolved in trimethyl orthoformate(0.2 mL) and a catalytic amount of camphor sulfonic acid was added. Thereaction mixture was refluxed for 4 h. The volatiles were removed underreduced pressure and the crude product was purified by columnchromatography to obtain tert-butyl[1-(1,2,4-oxadiazol-3-ylmethyl)tricyclo[3.3.1.0^(3,7)]non-3-yl]carbamate(0.15 g) in 51% yield as viscous liquid. m/z (M+1), 320; ¹H NMR (CDCl₃)300 MHz δ 8.62 (s, 1H), 4.71 (bs, 1H), 2.79 (s, 2H), 2.48-2.38 (m, 1H),2.35-2.28 (m, 1H), 2.10-1.88 (m, 4H), 1.74 (dd, J=2.8, 10.5 Hz, 2H),1.65-1.38 (m, 4H), 1.43 (s, (H).

Step III: To a stirred solution of the compound obtained from step II(0.15 g, 0.47 mmol) in CH₂Cl₂ (2 mL) cooled to 0° C. was addedtrifluoroacetic acid (0.5 mL). The reaction mixture was gradually warmedto room temperature and stirred for 1 h. The volatiles were removedunder reduced pressure and the residue was triturated several times withether to obtain1-(1,2,4-oxadiazol-3-ylmethyl)tricyclo[3.3.1.0^(3,7)]nonan-3-amine,trifluoroacetic acid salt as a white powder (0.12 g) in 77% yield. m/z(M+1), 220; ¹H NMR (DMSO-d₆) 300 MHz δ 9.53 (s, 1H), 8.09 (bs, 3H), 2.78(s, 2H), 2.38-2.25 (m, 2H), 1.88-1.70 (m, 6H), 1.60-1.42 (m, 4H).

Step IV: To a stirred solution of the compound obtained from step III(0.12 g, 0.36 mmol) in DMSO (1.5 mL) at room temperature under nitrogenatmosphere was added, (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile(0.06 g, 0.0.36 mmol) and K₂CO₃ (0.2 g, 1.44 mmol). After stirring thereaction mixture for 3 h, it was diluted with EtOAc and washed withwater and brine, dried over Na₂SO₄, and the solvent was removed underreduced pressure. The crude product was purified by columnchromatography to obtain((2S)-1-{N-[2-(1,2,4-oxadiazol-3-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrileas an off-white solid (0.05 g) in 40% yield. m/z (M+1), 356; 1H NMR(CDCl₃) 300 MHz δ 8.64 (s, 1H), 4.84-4.75 (m, 1H), 3.75-3.40 (m, 2H),3.49 (s, 2H), 2.81 (s, 2H), 2.40-2.10 (m, 6H), 1.92-1.70 (m, 6-H),1.68-1.48 (m, 4H).

Example 31A

Hydrochloride salt: To a stirred solution of the compound obtained fromexample 31 (20 mg, 0.056 mmol) in methanol (1 mL) cooled to 0° C. wasadded TMS-Cl (15 μL, 0.12 mmol). After 30 minutes, the volatiles wereremoved under reduced pressure and the residue was triturated severaltimes with ether to obtain the hydrochloride salt of the compound as anoff-white solid (21 mg).

Example 32

Step I: To a stirred suspension of NaH (50% dispersed in nujol, 50 mg,1.05 mmol) in THF (3 mL) cooled to 0° C., under N₂ atmosphere was addeddrop-wise with a syringe a solution of the compound obtained in Example19, step I (0.3 g, 0.7 mmol) in THF (4 mL). After stirring the reactionmixture at room temperature for 30 minutes, it was cooled again toice-bath temperature and MeI (0.1 mL, 1.5 mmol) was added. The reactionmixture was slowly warmed to room temperature and stirred for 2 h.Excess NaH was quenched by adding aq. NH₄Cl solution after cooling thereaction mixture to ice-bath temperature. The two layers were separatedand the aqueous layer was extracted with EtOAc. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography to obtain tert-butyl[2-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate(250 mg) as an off-white solid in 80% yield. m/z (M+1), 446; ¹H NMR(CDCl₃) 300 MHz δ 7.48 (d, J=8.7 Hz, 2H), 7.43-7.30 (m, 5H), 7.28-7.18(m, 2H), 5.17-5.03 (m, 3H), 3.80 (t, J=7.2 Hz, 2H), 3.47 (t, J=7.2 Hz,2H), 2.91 (s, 3H), 2.61-2.52 (m, 1H), 2.48-2.40 (m, 1H), 2.32-1.55 (m,10H).

Step II: To a stirred solution of the compound obtained from step I(0.25 g, 0.56 mmol) in a 1:1-mixture of CH₂Cl₂ and MeOH (10 mL) wasadded Pd/C (10% w/w, 0.1 g) and stirred at room temperature under H₂atmosphere for 2 h. The reaction mixture was filtered through a pad ofcelite and the filtrate was concentrated under reduced pressure toobtain1-[4-(3a-aminohexahydro-2,5-methanopentalen-2(1H)-yl)phenyl]-3-methylimidazolidin-2-one(0.15 g) as an off-white solid in 86% yield. M.R. 227-230° C.; m/z(M+1), 312; IR cm-1 3416, 3249, 2964, 1682, 1519, 1485, 1261, 810; 1HNMR (CDCl₃+DMSO-d₆) 300 MHz δ 8.38 (bs, 2H), 7.47 (d, J=8.6 Hz, 2H),7.19 (d, J=8.6 Hz, 2H), 3.76 (t, J=7.4 Hz, 2H), 3.43 (t, J=7.4 Hz, 2H),2.77 (s, 3H), 2.48-2.40 (m, 2H), 2.22-2.14 (m, 1H), 2.10-2.0 (m, 2H),2.0-1.86 (m, 4H), 1.80-1.60 (m, 3H).

Step III: To a stirred mixture of the compound obtained from step II(0.15 g, 0.48 mmol) and K₂CO₃ (0.21 g, 1.5 mmol) in DMSO (2 mL) at icebath temperature was added compound(S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.5 mmol).The reaction mixture was gradually warmed to room temperature andstirred for 3 h. Upon completion of the reaction (checked by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, and the solvent was removed under reduced pressure.The crude product was purified by column chromatography to obtain((2S)-1-{N-[2-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrileas an off-white solid (0.09 g) in 42% yield. m/z (M+1) 449; ¹H NMR(CDCl₃) 300 MHz δ 7.47 (d, J=8.6 Hz, 2H), 7.22 (t, J=8.6 Hz, 2H),4.85-4.76 (m, 1H), 3.79 (t, J=7.3 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s,2H), 2.89 (s, 3H), 2.46-2.39 (m, 1H), 2.36-2.15 (m, 3H), 2.12-1.58 (m,12H).

1. A compound of formula I,

its tautomeric forms, stereoisomers, diastereomers, and pharmaceuticallyacceptable salts, wherein: X=CH₂, CHF, CF₂, CHCl, CHOH, CHOCH₃, CHPh;Y=CN; R₁ and R₅ are selected from hydrogen, C₁-C₄ alkyl, and hydroxy; R₂is selected from hydrogen, C₁-C₄ alkyl, substituted alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, R₅NHC₁₋₄ alkyl, and R₅NHC(NH)NHC₁₋₄alkyl; R₃ is selected from hydrogen and C₁-C₄ alkyl; R₄ is selected fromhydrogen, C₁-C₄ alkyl, substituted alkyl, C₁-C₄ alkoxy, C₁-C₄alkanoyloxy, hydroxy, amino, nitro, C₂-C₆ alkenyl, acyl, and halogen;n=1 or 2; m=0, 1, or 2; R=R₁₁, R₁₂, or R₁₃, in which R₁₁ is at least onegroup selected from the below a), b), or c), whereupon the at least onegroup is linked to the nor-adamantyl moiety either directly or via amethylene or ethylene adjacent, either by C—C linkage or by C—N linkage;a) cycloalkyl group, which is optionally substituted by C₁-C₄ alkyl,dialkyl, or oxo, b) optionally substituted heteroaryl group, wherein thesubstituents of the heteroaryl group are selected from a groupconsisting of R₆ and R₇, wherein R₆ is hydrogen, C₁-C₄ alkyl, C₂-C₄alkenyl, hydroxy, hydroxy alkyl, alkylamino, haloalkyl, amino, acyl,COOR₉, or COR₉, and R₇ is selected from a group consisting of hydrogen,hydroxy, halogen, amino, nitro, C₁-C₈ alkyl, C₂-C₄ alkenyl, COOR₉,CONR₈R₉, COR₉, NHCOOR₈, NHS(O)₂R₈, NHS(O)R₈, NHS(O)₂NHR₈, NR₈COOR₉,NR₈COR₉, NR₈S(O)₂R₉, NR₈CONR₈R₉, NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, OSO₂R₈,OCONR₈R₉, SO₂R₈, SOR₈, SR₈, SO₂NR₈R₉, S(O)₂OR₈, and when R₆ and R₇ arepresent on adjacent carbons of the ring system, they may together form asix membered aromatic ring or a heterocyclic ring with furthersubstitutions; c) heterocyclyl group optionally substituted by C₁-C₃alkyl, dialkyl and oxo groups, wherein the heterocyclic ring system is a4- to 10-membered mono- or bicyclic ring system with one or moreheteroatoms selected from the group consisting of nitrogen, sulfur, andoxygen and functional groups thereof wherein the heterocyclic ringsystem contains no, one, or two double bonds, R₁₂ is selected fromhydrogen, halogen, haloalkyl, hydroxy, carboxy, nitro, amino, cyano,alkyl sulfinyl, alkylsulfonyl, alkylthio, amidinyl, alkoxy, alkoxycarbonylamino, ureido, thiureido, alkanoyl, alkanoyloxy, alkanoyl amino,carbamoyl, guanidyl, optionally substituted C₁-C₈ alkyl, and C₂-C₆alkenyl; R₁₃ is optionally substituted aryl, wherein at least one of thesubstituents thereof comprises at least one group selected from a)hydrogen; b) C₁-C₈ alkyl, C₂-C₆ alkenyl, halo, alkylhalo, alkoxy,alkylsulfonyl, alkylsulfinyl, alkoxy, alkanoyl, alkanoyloxy, acylamino,carbonylamino, guanidyl, nitro, amino, COOR₉, R₈NHC(O)R₉, COR₉, CONR₈R₉,NHC(O)OR₈, NHC(O)R₈, NHC(O)NR₈R₉, NHC(O)NR₈R₉, NHS(O)₂R₈, NHS(O)R₈,NHS(O)₂NHR₈, NHS(O)₂NHC(O)R₈, NR₈COOR₉, NR₈COR₉, NR₈S(O)₂R₉, NR₈CONR₈R₉,NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, S(O)₂R₈, SOR₈, SR₈, S(O)₂NR₈R₉, OCF₃,OS(O)₂R₈, or OC(O)NR₈R₉; c) saturated, partially saturated, orunsaturated, mono- or bicyclic heterocyclic ring system optionallysubstituted by one or more groups selected from C₁-C₃ alkyl, C₂-C₆alkenyl, dialkyl, and oxo, wherein the heterocyclic ring system is a 4-to 10-membered ring with one or more heteroatoms selected from the groupconsisting of nitrogen, sulfur, and oxygen and functional groupsthereof; wherein R₈, R₉, and R₁₀, which are optionally substituted byhalogen, hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy,hydroxyalkyl, amino, alkylthio, or thioalkyl groups, are individuallyselected from hydrogen, optionally substituted C₁-C₈ alkyl, aryl,arylalkyl, alkoxy carbonyl, and arylalkoxy carbonyl and when R₈ and R₉are present together on a nitrogen atom they form a 5- or 6-memberedsaturated, partially unsaturated, or unsaturated cyclic systemcontaining carbon atoms, at least one nitrogen atom and optionally oneor more other heteroatoms selected from oxygen, sulfur, and nitrogen. 2.A compound of formula I according to claim 1, wherein R=R₁₁ and R₁₁ isat least one C₄-C₇ cycloalkyl group, which is optionally substituted byC₁-C₄ alkyl, dialkyl, or oxo.
 3. A compound of formula I according toclaim 1, wherein R=R₁₁ and R₁₁ is at least one C₅-C₆ cycloalkyl group,which is optionally substituted by C₁-C₄ alkyl, dialkyl, or oxo.
 4. Acompound of formula I according to claim 1, wherein R=R₁₁ and R₁₁ is atleast one 4 to 6-membered, mono-heterocyclic ring system with one ormore heteroatoms selected from the group consisting of nitrogen, sulfur,and oxygen and functional groups thereof, wherein the heterocyclic ringsystem is optionally substituted by C₁-C₃ alkyl, dialkyl and oxo groupsand contains no, one, or two double bonds.
 5. A compound of formula Iaccording to claim 1, wherein R=R₁₁ and R₁₁ is at least one optionallysubstituted 5 to 10 membered heteroaryl ring system, in which theheteroaryl ring system is a monocyclic aromatic ring system or abicyclic aromatic ring system comprising one, two, or more heteroatomsselected from nitrogen, sulfur, and oxygen, and wherein the substituentsof the heteroaryl ring system are selected from a group consisting of R₆and R₇, wherein R₆ is hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, hydroxy,hydroxy alkyl, alkylamino, haloalkyl, amino, acyl, COOR₉, or COR₉, andR₇ is selected from a group consisting of hydrogen, hydroxy, halogen,amino, nitro, C₁-C₈ alkyl, C₂-C₄ alkenyl, COOR₉, CONR₈R₉, COR₉, NHCOOR₈,NHS(O)₂R₈, NHS(O)R₈, NHS(O)₂NHR₈, NR₈COOR₉, NR₈COR₉, NR₈S(O)₂R₉,NR₈CONR₈R₉, NR₈C(S)NR₈R₉, NHC(O)NHS(O)₂R₈, OSO₂R₈, OCONR₈R₉, SO₂R₈,SOR₈, SR₈, SO₂NR₈R₉, S(O)₂OR₈, and when R₆ and R₇ are present onadjacent carbons of the ring system, they may together form a sixmembered aromatic ring or a heterocyclic ring with furthersubstitutions.
 6. A compound of formula Ia as claimed in claim 1

its tautomeric forms, stereoisomers, diastereomers, and pharmaceuticallyacceptable salts, wherein X=CH₂, CHF; Y=CN; R₃ is independently selectedfrom hydrogen and C₁-C₄ alkyl; R₄ is selected from hydrogen, C₁-C₄alkyl, substituted alkyl, C₁-C₄ alkoxy, C₁-C₄ alkanoyloxy, hydroxy,amino, nitro, C₂-C₆ alkenyl, acyl, and halogen; n=1 or 2; m=0, 1, or 2;R is R₁₁, R₁₂, or R₁₃; and wherein R₁₁, R₁₂, and R₁₃ are as defined inclaim
 1. 7. A compound according to claim 1, wherein R is R₁₁; m is 1;R₃ is hydrogen; R₄ is hydrogen; n is 1; Y is CN; X is CH₂, CHF; and R₁₁is as defined in claim
 1. 8. A compound according to claim 1, wherein Ris R₁₁ or R₁₂; m is 0; R₁, R₂, R₃, and R₄ are hydrogen; n is 1; Y is CN;X is CH₂, CHF; and R₁₁ and R₁₂ are as defined in claim
 1. 9. A compoundaccording to claim 1, wherein R is R₁₃; m is 0; R₁, R₂, R₃, and R₄ arehydrogen; n is 1; Y is CN; X is CH₂, CHF; and R₁₃ is as defined inclaim
 1. 10. A compound according to claim 1, wherein the compound isselected from(2S)-1-[1H-1,2,4-triazol-1-ylmethyl-(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S,4S)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S,4R)-4-fluoro-1-{N-[2-(1H-1,2,4-triazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;((2S)-1-{N-[2-(1,2,4-oxadiazol-3-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S,4R)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S,4S)-4-fluoro-1-{N-[2-[4-(2-oxopyrrolidin-1-1)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;((2S)-1-{N-[2-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidin-2-yl)acetonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-[(tricyclo[3.3.1.0^(3,7)]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{[(1-hydroxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{[(1-methoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{[(1-ethoxytricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{[(1-aminotricyclo[3.3.1.0^(3,7)]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate;(2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate; and(2S)-1-{N-[2-(4-aminophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrileor its salts in its single enantiomeric form or as a racemate.
 11. Aprocess for the preparation of a compound of claim 1, which processcomprises the steps of: coupling a compound of formula II, which is inits free form, in a form of a salt, or in a protected form, with acompound of formula III

wherein P is hydrogen or a protecting group, L is a leaving group, andR, R₁, R₂, R₃, R₄, X, Y, n, and m are as defined in claim
 1. 12. Apharmaceutical composition comprising a compound of claim 1 and at leastone pharmaceutically acceptable carrier, diluent, or excipient.
 13. Amethod for the treatment of diseases which are associated with DPP-IV,selected from the group consisting of type II diabetes, diabeticcomplications as well as for the treatment of dislipidemia,hypercholesterolemia, obesity and hyperglycemia which method comprisesadministering to a host suffering therefrom a therapeutically effectiveamount of a compound according to claim
 1. 14. A compound of formula Iaccording to claim 1 wherein, when R₆ and R₇ are present on adjacentcarbons of the ring system, they together form a phenyl ring.
 15. Acompound of formula I according to claim 1 wherein, when R₆ and R₇ arepresent on adjacent carbons of the ring system they form a pyridineheterocyclic ring.